A list of all the studies on epilepsy and cannabinoids

Science & Medical

This is a list of all the studies published on Epilepsy and cannabis.

With a growing awareness of the potential benefits of cannabis as a medical treatment for those who have been diagnosed with a form of epilepsy or seizure disorder, we thought it would be a good idea to help arm our readers with as much knowledge as possible on the subject.

We are constantly told that there is not enough research on any medical condition when it comes to cannabis, but anyone that knows how to search for published medical studies using google knows that this just isn’t the case!

Our team of clinical researchers and medical professionals have compiled this list of over 100 published studies on cannabinoids and epilepsy. It is well worth a browse of the many study titles just to get an idea of what kind of research has taken place.

If you have epilepsy, we encourage you to take a read of the intro and conclusion of the studies that interest you in order to gain perspective of what the study involved and what the scientist found with some of their thoughts about what it could mean or lead on to for further studies. This can give you a foot up when talking to your neurologist about looking at cannabinoid treatment options if you are one of the many patients that have already been trying the AED (anti epileptic drugs) that are prescribed as conventional treatment.

Epilepsy is a disorder that impacts the lives of children and adults with over 500,000 having the diagnosis in the UK. Current medications include, sodium valproate, carbamazepine, lamotrigine, levetiracetam, oxcarbazepine, ethosuximide, topiramate. These have side effects of drowsiness, a lack of energy, agitation, headaches, uncontrollable shaking (tremor), hair loss or unwanted hair growth, swollen gums, sickness and rashes.

Cannabis oil is a natural plant extract which main active ingredient compounds are THC (delta 9 tetrahydrocannabinol) and CBD (cannabidiol). Patients with different forms of epilepsy find that the ratios needed vary from patient to patient and there is no one size fits all cannabis medicine for anyone. It requires a level of self titration and this is an area most patients or parents treating a child have concern over.

Cannabis Social Clubs have become a first point of contact for many patients in the UK who operate shared cultivation collectives or the ability to access safe cannabis oils that have been tested by a lab, These lab tests allow patients to know the mg of THC in the extract so that tinctures and other cannabis preparations can be made with consistent dosing batch to batch and crop to crop.

Some members find that cannabis extracts have kept them in remission for a number of years and free of all seizures, others have found that it has reduced them greatly but not completely.

So, take a look below at this giant list of evidence to show the potential benefit and interactions of cannabis with epilepsy.

Medical Cannabis and Epilepsy

1. Cannabinoid therapy in epilepsy.

2. Epidiolex (Cannabidiol): A New Hope for Patients With Dravet or Lennox-Gastaut Syndromes.

3. Successful use of pure cannabidiol for the treatment of super-refractory status epilepticus.

4. Cannabidiol reduces seizures and associated behavioral comorbidities in a range of animal seizure and epilepsy models.

5. Long-term cannabidiol treatment in patients with Dravet syndrome: An open-label extension trial.

6. CB2R induces a protective response for epileptic seizure via the PI3K 110α-AKT signaling pathway.

7. Simultaneous quantification of thirteen cannabinoids and metabolites in human plasma by liquid chromatography tandem mass spectrometry in adult epilepsy patients.

8. Cannabis-based products for pediatric epilepsy: A systematic review.

9. Emerging drugs for the treatment of Dravet syndrome.

10. Long-Term Safety, Tolerability, and Efficacy of Cannabidiol in Children with Refractory Epilepsy: Results from an Expanded Access Program in the US.

11. Cannabis for the treatment of paediatric epilepsy? An update for Canadian paediatricians.

12. Epilepsy and Cannabis: A Literature Review.

13. The Endocannabinoid System and Oligodendrocytes in Health and Disease.

14. Cannabis Therapeutics and the Future of Neurology.

15. Efficacy of cannabinoids in paediatric epilepsy.

16. Medical cannabis: A needs analysis for people with epilepsy.

17. Efficacy and Safety of Cannabidiol in Epilepsy: A Systematic Review and Meta-Analysis.

18. Cannabis and epilepsy.

19. Potential Clinical Benefits of CBD-Rich Cannabis Extracts Over Purified CBD in Treatment-Resistant Epilepsy: Observational Data Meta-analysis.

20. Cannabidiol for Treatment of Childhood Epilepsy-A Cross-Sectional Survey.

21. A prospective open-label trial of a CBD/THC cannabis oil in dravet syndrome.

22. Inhibitory effects of cannabidiol on voltage-dependent sodium currents.

23. Cannabis for the Treatment of Epilepsy: an Update.

24. Anticonvulsant and Neuroprotective Effects of Cannabidiol During the Juvenile Period.

25. Cannabidiol for Epilepsy: New Hope on the Horizon?

26. Cannabinoid signalling in the immature brain: Encephalopathies and neurodevelopmental disorders.

27. Cannabinoid-Based Therapies and Brain Development: Potential Harmful Effect of Early Modulation of the Endocannabinoid System.

28. Cannabidiol improves frequency and severity of seizures and reduces adverse events in an open-label add-on prospective study.

29. Cannabidiol for treating drug-resistant epilepsy in children: the New South Wales experience.

30. Cannabis for pediatric epilepsy: protocol for a living systematic review.

31. Open-label use of highly purified CBD (Epidiolex®) in patients with CDKL5 deficiency disorder and Aicardi, Dup15q, and Doose syndromes.

32. Long-term safety and treatment effects of cannabidiol in children and adults with treatment-resistant epilepsies: Expanded access program results.

33. The protocol for the Cannabidiol in children with refractory epileptic encephalopathy (CARE-E) study: a phase 1 dosage escalation study.

34. Composition and Use of Cannabis Extracts for Childhood Epilepsy in the Australian Community.

35. The adult motor phenotype of Dravet syndrome is associated with mutation of the STXBP1 gene and responds well to cannabidiol treatment.

36. Addition of Cannabidiol to Current Antiepileptic Therapy Reduces Drop Seizures in Children and Adults With Treatment-Resistant Lennox-Gastaut Syndrome.

37. Investigational cannabinoids in seizure disorders, what have we learned thus far?

38. Review of the neurological benefits of phytocannabinoids.

39. Effect of Cannabidiol on Drop Seizures in the Lennox-Gastaut Syndrome.

40. Efficacy of CBD-enriched medical cannabis for treatment of refractory epilepsy in children and adolescents – An observational, longitudinal study.

41. Treatment Strategies for Dravet Syndrome.

42. Cannabidiol exerts antiepileptic effects by restoring hippocampal interneuron functions in a temporal lobe epilepsy model.

43. Randomized, dose-ranging safety trial of cannabidiol in Dravet syndrome.

44. Cannabidiol for treatment of refractory childhood epilepsies: Experience from a single tertiary epilepsy center in Slovenia.

45. Evidence for cannabis and cannabinoids for epilepsy: a systematic review of controlled and observational evidence.

46. Cannabidiol Regulates Long Term Potentiation Following Status Epilepticus: Mediation by Calcium Stores and Serotonin.

47. Cannabis for paediatric epilepsy: challenges and conundrums.

48. Cannabidiol in patients with seizures associated with Lennox-Gastaut syndrome (GWPCARE4): a randomised, double-blind, placebo-controlled phase 3 trial.

49. Prospects of Cannabidiol for Easing Status Epilepticus-Induced Epileptogenesis and Related Comorbidities.

50. Cannabinoids in the Treatment of Epilepsy: Hard Evidence at Last?

51. Do Cannabinoids Confer Neuroprotection Against Epilepsy? An Overview.

52. Cannabinoids for epilepsy: What do we know and where do we go?

53. Efficacy and safety of cannabis for treating children with refractory epilepsy.

54. The use of cannabidiol for seizure management in patients with brain tumor-related epilepsy.

55. Medical Cannabinoids in Children and Adolescents: A Systematic Review.

56. A resurging boom in new drugs for epilepsy and brain disorders.

57. [Cannabis use in Epilepsy. Current situation in Argentina and abroad].

58. The potential role of cannabinoids in epilepsy treatment.

59. Interactions between cannabidiol and commonly used antiepileptic drugs.

60. Could Cannabidiol be a Treatment Option for Intractable Childhood and Adolescent Epilepsy?

61. [Cannabidiol: its use in refractory epilepsies].

62. Assessing the role of serotonergic receptors in cannabidiol’s anticonvulsant efficacy.

63. Quality of Life in Childhood Epilepsy in pediatric patients enrolled in a prospective, open-label clinical study with cannabidiol.

64. Trial of Cannabidiol for Drug-Resistant Seizures in the Dravet Syndrome.

65. Cannabidiol in Patients With Intractable Epilepsy Due to TSC: A Possible Medication But Not a Miracle.

66. Treatment-resistant Lennox-Gastaut syndrome: therapeutic trends, challenges and future directions.

67. Cannabidiol Treatment for Refractory Seizures in Sturge-Weber Syndrome.

68. Neurological Disorders in Medical Use of Cannabis: An Update.

69. Neurological Aspects of Medical Use of Cannabidiol.

70. Report from a Survey of Parents Regarding the Use of Cannabidiol (Medicinal cannabis) in Mexican Children with Refractory Epilepsy.

71. The current status of artisanal cannabis for the treatment of epilepsy in the United States.

72. An Australian nationwide survey on medicinal cannabis use for epilepsy: History of antiepileptic drug treatment predicts medicinal cannabis use.

73. Social correlates of health status, quality of life, and mood states in patients treated with cannabidiol for epilepsy.

74. Therapeutic effects of cannabinoids in animal models of seizures, epilepsy, epileptogenesis, and epilepsy-related neuroprotection.

75. Treatment issues for children with epilepsy transitioning to adult care.

76. Cannabinoids in treatment-resistant epilepsy: A review.

77. Are cannabinoids effective for epilepsy?

78. Neuroimaging studies towards understanding the central effects of pharmacological cannabis products on patients with epilepsy.

79. Historical perspective on the medical use of cannabis for epilepsy: Ancient times to the 1980s.

80. Pharmacology of cannabinoids in the treatment of epilepsy.

81. Cannabis and epilepsy: An ancient treatment returns to the fore.

82. Duration of use of oral cannabis extract in a cohort of pediatric epilepsy patients.

83. Δ9-THC Intoxication by Cannabidiol-Enriched Cannabis Extract in Two Children with Refractory Epilepsy: Full Remission after Switching to Purified Cannabidiol.

84. Cannabidiol as a new treatment for drug-resistant epilepsy in tuberous sclerosis complex.

85. Cannabidiol as a Potential Treatment for Febrile Infection-Related Epilepsy Syndrome (FIRES) in the Acute and Chronic Phases.

86. From Cannabis to Cannabidiol to Treat Epilepsy, Where Are We?

87. The Utility of Cannabidiol in the Treatment of Refractory Epilepsy.

88. Cannabidiol and epilepsy: Rationale and therapeutic potential.

89. Is the medical use of cannabis a therapeutic option for children?

90. Plant-Derived and Endogenous Cannabinoids in Epilepsy.

91. Cannabinoids for pediatric epilepsy? Up in smoke or real science?

92. CBD-enriched medical cannabis for intractable pediatric epilepsy: The current Israeli experience.

93. The Pharmacological Basis of Cannabis Therapy for Epilepsy.

94. Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial.

95. Cannabidiol as potential treatment in refractory pediatric epilepsy.

96. TRPV1 Channel: A Potential Drug Target for Treating Epilepsy.

97. Cannabis and Endocannabinoid Signaling in Epilepsy.

98. Marijuana Use in Epilepsy: The Myth and the Reality.

99. Cannabinoids and Epilepsy.

100. Cannabinoids: is there a potential treatment role in epilepsy?

101. Drug-drug interaction between clobazam and cannabidiol in children with refractory epilepsy.

102. Perceived efficacy of cannabidiol-enriched cannabis extracts for treatment of pediatric epilepsy: A potential role for infantile spasms and Lennox-Gastaut syndrome.

103. Use of cannabis in severe childhood epilepsy and child protection considerations.

104. Pure cannabidiol in the treatment of malignant migrating partial seizures in infancy: a case report.

105. Parental reporting of response to oral cannabis extracts for treatment of refractory epilepsy.

106. Phytocannabinoids and epilepsy.

107. Medical marijuana in neurology.

108. Fewer specialists support using medical marijuana and CBD in treating epilepsy patients compared with other medical professionals and patients: result of Epilepsia’s survey.

109. Seizing an opportunity for the endocannabinoid system.

110. Cannabis, cannabidiol, and epilepsy–from receptors to clinical response.

111. Nonpsychotropic plant cannabinoids, cannabidivarin (CBDV) and cannabidiol (CBD), activate and desensitize transient receptor potential vanilloid 1 (TRPV1) channels in vitro: potential for the treatment of neuronal hyperexcitability.

112. Cannabidiol: pharmacology and potential therapeutic role in epilepsy and other neuropsychiatric disorders.

113. The case for medical marijuana in epilepsy.

114. Systematic review: efficacy and safety of medical marijuana in selected neurologic disorders: report of the Guideline Development Subcommittee of the American Academy of Neurology.

115. Cannabinoids for epilepsy.

116. Report of a parent survey of cannabidiol-enriched cannabis use in pediatric treatment-resistant epilepsy.

117. Cannabis and other illicit drug use in epilepsy patients.

118. Seizure exacerbation in two patients with focal epilepsy following marijuana cessation.

119. Cannabinoids for epilepsy.

120. Cannabidiol for neurodegenerative disorders: important new clinical applications for this phytocannabinoid?

121. Statistical parametric mapping reveals regional alterations in cannabinoid CB1 receptor distribution and G-protein activation in the 3D reconstructed epileptic rat brain.

122. Marijuana, endocannabinoids, and epilepsy: potential and challenges for improved therapeutic intervention.

123. Cerebrospinal fluid levels of the endocannabinoid anandamide are reduced in patients with untreated newly diagnosed temporal lobe epilepsy.

124. Temporal characterization of changes in hippocampal cannabinoid CB(1) receptor expression following pilocarpine-induced status epilepticus.

125. Potential therapeutical effects of cannabidiol in children with pharmacoresistant epilepsy.

126. The endocannabinoid system controls key epileptogenic circuits in the hippocampus.

127. Not too excited? Thank your endocannabinoids.

128. Endocannabinoids and their implications for epilepsy.

129. Cannabinoids as potential anti-epileptic drugs.

130. On-demand activation of the endocannabinoid system in the control of neuronal excitability and epileptiform seizures.

131. Marijuana use and epilepsy: prevalence in patients of a tertiary care epilepsy center.

132. On the application of cannabis in paediatrics and epileptology.

133. The endogenous cannabinoid system regulates seizure frequency and duration in a model of temporal lobe epilepsy.

134. Cannabinoid receptor-1 activation suppresses inhibitory synaptic activity in human dentate gyrus.

135. Alcohol and marijuana: effects on epilepsy and use by patients with epilepsy.

136. Hypnotic and antiepileptic effects of cannabidiol.

137. The cannabinoids as potential antiepileptics.

138. Chronic administration of cannabidiol to healthy volunteers and epileptic patients.

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138 of 138 saved results

1. Cannabinoid therapy in epilepsy.

Author(s): Billakota S; Devinsky O; Marsh E

Source: Current opinion in neurology; Jan 2019

Publication Date: Jan 2019

Publication Type(s): Journal Article

PubMedID: 30676535

Abstract:PURPOSE OF REVIEW: To review the history, pharmacology, and clinical science of cannabidiol (CBD) in the treatment of epilepsy.RECENT FINDINGS: Phase III randomized controlled trials and prospective open label trials have provided efficacy and safety data for the use of CBD in pediatric onset severe epilepsies. The product that was studied in the vast majority of these published trials, Epidiolex (>99% of CBD and <0.10% Δ9-tetrahydrocannabinol (THC); GW pharmaceuticals, Cambridge, UK), has now been FDA approved based on this published data.SUMMARY: Identification of CBD, Δ9-THC, and the endocannabinoid system in the mid-20th century has led to advancement of cannabis-based therapies for epilepsy. Based on clinical trial data, Epidiolex is the first CBD medication approved by a national regulatory agency (US Food and Drug Administration for Dravet and Lennox Gastaut syndrome; European Medicines Agency for Lennox Gastaut syndrome). Approval of CBD as a treatment for these rare and severe pediatric-onset epilepsy syndromes is an important milestone, but the complete spectrum of use of cannabis-derived products, and the use of CBD for other epilepsy syndromes remains to be determined.

Database: PubMed

2. Epidiolex (Cannabidiol): A New Hope for Patients With Dravet or Lennox-Gastaut Syndromes.

Author(s): Chen JW; Borgelt LM; Blackmer AB

Source: The Annals of pharmacotherapy; Jan 2019 ; p. 1060028018822124

Publication Date: Jan 2019

Publication Type(s): Journal Article

PubMedID: 30616356

Abstract:OBJECTIVE: To review the efficacy, safety, pharmacology and pharmacokinetics of pure, plant-derived cannabidiol (CBD; Epidiolex) in the treatment of Dravet syndrome (DS) and Lennox-Gastaut syndrome (LGS).DATA SOURCES: Relevant information was identified through EMBASE and Ovid MEDLINE (1946 to October 2018). Product labeling and https://www.clinicaltrials.gov were also reviewed.STUDY SELECTION/DATA EXTRACTION: English language articles evaluating efficacy and safety in humans with treatment-resistant epilepsies were reviewed; additional pharmacology and pharmacokinetic studies in humans, animals, and in vitro were also included.DATA SYNTHESIS: Pure, plant-based CBD is a pharmaceutical grade extract that exhibits clinically significant antiseizure properties, with a hypothesized multimodal mechanism of action. In the GWPCARE trial series, CBD displayed superior efficacy in reducing key seizure frequencies (convulsive seizures in DS; drop seizures in LGS) by 17% to 23% compared with placebo as adjunctive therapy to standard antiepileptic drugs in patients 2 years of age and older. Common adverse effects were somnolence, diarrhea, and elevated hepatic transaminases. Noteworthy drug-drug interactions included clobazam, valproates, and significant inducers/inhibitors of CYP2C19 and 3A4 enzymes. Relevance to Patient Care and Clinical Practice: A discussion regarding CBD dosing, administration, adverse effects, monitoring parameters, and interactions is provided to guide clinicians. CBD offers patients with DS and LGS a new treatment option for refractory seizures.CONCLUSION: This is the first cannabis-derived medication with approval from the US Food and Drug Administration. This CBD formulation significantly reduces seizures as an adjunct to standard antiepileptic therapies in patients ≥2 years old with DS and LGS and is well tolerated.

Database: PubMed

3. Successful use of pure cannabidiol for the treatment of super-refractory status epilepticus.

Author(s): Rajaraman RR; Sankar R; Hussain SA

Source: Epilepsy & behavior case reports; 2018; vol. 10 ; p. 141-144

Publication Date: 2018

Publication Type(s): Journal Article

PubMedID: 30596011

Available  at Epilepsy & behavior case reports –  from Europe PubMed Central – Open Access

Abstract:We present the case of a child with long-standing, super-refractory status epilepticus (SRSE) who manifested prompt and complete resolution of SRSE upon exposure to pure cannabidiol. SRSE emerged in the context of remote suspected encephalitis with previously well-controlled epilepsy. We discuss the extent to which response may be specifically attributed to cannabidiol, with consideration and discussion of multiple potential drug-drug interactions. Based on this case, we propose that adjunctive cannabidiol be considered in the treatment of SRSE.

Database: PubMed

4. Cannabidiol reduces seizures and associated behavioral comorbidities in a range of animal seizure and epilepsy models.

Author(s): Patra PH; Barker-Haliski M; White HS; Whalley BJ; Glyn S; Sandhu H; Jones N; Bazelot M; Williams CM; McNeish AJ

Source: Epilepsia; Dec 2018

Publication Date: Dec 2018

Publication Type(s): Journal Article

PubMedID: 30588604

Available  at Epilepsia –  from Wiley

Available  at Epilepsia –  from IngentaConnect

Abstract:OBJECTIVE: Epilepsy is a progressive neurological disease characterized by recurrent seizures and behavioral comorbidities. We investigated the antiseizure effect of cannabidiol (CBD) in a battery of acute seizure models. Additionally, we defined the disease-modifying potential of chronic oral administration of CBD on associated comorbidities in the reduced intensity status epilepticus-spontaneous recurrent seizures (RISE-SRS) model of temporal lobe epilepsy (TLE).METHODS: We evaluated the acute antiseizure effect of CBD in the maximal electroshock seizure, 6-Hz psychomotor seizure, and pentylenetetrazol acute seizure tests, as well as the corneal kindling model of chronic seizures in mice following intraperitoneal administration. Median effective or behavioral toxic dose was determined in both mice and rats. Next, we tested an intravenous preparation of CBD (10 mg/kg single dose) in a rat model of pilocarpine-induced status epilepticus. We defined the effect of chronic CBD administration (200 mg/kg orally) on spontaneous seizures, motor control, gait, and memory function in the rat RISE-SRS model of TLE.RESULTS: CBD was effective in a battery of acute seizure models in both mice and rats following intraperitoneal administration. In the pilocarpine-induced status epilepticus rat model, CBD attenuated maximum seizure severity following intravenous administration, further demonstrating CBD’s acute antiseizure efficacy in this rat model. We established that oral CBD attenuated the time-dependent increase in seizure burden and improved TLE-associated motor comorbidities of epileptic rats in the RISE-SRS model without affecting gait. Chronic administration of CBD after the onset of SRS ameliorated reference memory and working memory errors of epileptic animals in a spatial learning and memory task.SIGNIFICANCE: The present study illustrates that CBD is a well-tolerated and effective antiseizure agent and illustrates a potential disease-modifying effect of CBD on reducing both seizure burden and associated comorbidities well after the onset of symptomatic seizures in a model of TLE.

Database: PubMed

5. Long-term cannabidiol treatment in patients with Dravet syndrome: An open-label extension trial.

Author(s): Devinsky O; Nabbout R; Miller I; Laux L; Zolnowska M; Wright S; Roberts C

Source: Epilepsia; Dec 2018

Publication Date: Dec 2018

Publication Type(s): Journal Article

PubMedID: 30582156

Available  at Epilepsia –  from Wiley

Available  at Epilepsia –  from IngentaConnect

Abstract:OBJECTIVE: Add-on cannabidiol (CBD) significantly reduced seizures associated with Dravet syndrome (DS) in a randomized, double-blind, placebo-controlled trial: GWPCARE1 Part B (NCT02091375). Patients who completed GWPCARE1 Part A (NCT02091206) or Part B, or a second placebo-controlled trial, GWPCARE2 (NCT02224703), were invited to enroll in a long-term open-label extension trial, GWPCARE5 (NCT02224573). We present an interim analysis of the safety, efficacy, and patient-reported outcomes from GWPCARE5.METHODS: Patients received a pharmaceutical formulation of highly purified CBD in oral solution (100 mg/mL), titrated from 2.5 to 20 mg/kg/d over a 2-week period, with their existing medications. Based on response and tolerance, CBD could be reduced or increased up to 30 mg/kg/d.RESULTS: By November 2016, a total of 278 patients had completed the original randomized trials, and 264 (95%) enrolled in this open-label extension. Median treatment duration was 274 days (range 1-512) with a mean modal dose of 21 mg/kg/d, and patients received a median of 3 concomitant antiepileptic medications. Adverse events (AEs) occurred in 93.2% of patients and were mostly mild (36.7%) or moderate (39.0%). Commonly reported AEs were diarrhea (34.5%), pyrexia (27.3%), decreased appetite (25.4%), and somnolence (24.6%). Seventeen patients (6.4%) discontinued due to AEs. Twenty-two of the 128 patients from GWPCARE1 (17.2%), all taking valproic acid, had liver transaminase elevations ≥3 times the upper limit of normal. In patients from GWPCARE1 Part B, the median reduction from baseline in monthly seizure frequency assessed in 12-week periods up to week 48 ranged from 38% to 44% for convulsive seizures and 39% to 51% for total seizures. After 48 weeks of treatment, 85% of patients/caregivers reported improvement in the patient’s overall condition on the Subject/Caregiver Global Impression of Change scale.SIGNIFICANCE: This trial shows that long-term CBD treatment had an acceptable safety profile and led to sustained, clinically meaningful reductions in seizure frequency in patients with treatment-resistant DS.

Database: PubMed

6. CB2R induces a protective response for epileptic seizure via the PI3K 110α-AKT signaling pathway.

Author(s): Cao Q; Liu X; Yang F; Wang H

Source: Experimental and therapeutic medicine; Dec 2018; vol. 16 (no. 6); p. 4784-4790

Publication Date: Dec 2018

Publication Type(s): Journal Article

PubMedID: 30542433

Abstract:Epilepsy is a chronic brain disease caused by abnormal discharging in the brain, which induces momentary brain dysfunction. Cannabinoid 2 receptor (CB2R) is expressed in central nervous system (CNS) and serves an important role in the pathogenesis of CNS diseases. The aim of the present study was to explore the effects of CB2R activation on phosphoinositide 3-kinase (PI3K) 110α-protein kinase B (AKT) signaling in an astrocyte model of epilepsy. Rat CTX TNA2 astrocytes were treated with Mg free solution to establish a cell model of epilepsy and were subsequently treated with a CB2R agonist (JWH133) and antagonist (AM630). Cell cycle analysis revealed that treatment using Mg free solution inhibited cell cycle transition. JWH133 facilitated cell cycle progression while AM630 inhibited it. Western blotting results demonstrated that treatment with Mg free solution downregulated the expression of cyclin D1, cyclin E, phosphorylated Retinoblastoma (p-Rb), B-cell lymphoma 2 (Bcl-2), PI3K 110α, p-AKT and p-mammalian target of rapamycin, whereas JWH133 treatment upregulated these proteins. AM630 ameliorated the JWH133-induced upregulation of these proteins. To confirm the involvement of AKT signaling, the AKT inhibitor wortmannin was used. The results revealed that wortmannin inhibited the effect of JWH133 on p-AKT, cyclin D1, p-Rb and Bcl-2 expression. In addition, the effects of JWH133 and AM630 on PI3K 110α-AKT signaling were verified using a rat model of epilepsy. In conclusion, the present study demonstrates that CB2R activation induces astrocyte proliferation and survival via activation of the PI3K 110α-AKT signaling pathway.

Database: PubMed

7. Simultaneous quantification of thirteen cannabinoids and metabolites in human plasma by liquid chromatography tandem mass spectrometry in adult epilepsy patients.

Author(s): Roslawski MJ; Remmel RP; Karanam A; Leppik IE; Marino SE; Birnbaum AK

Source: Therapeutic drug monitoring; Dec 2018

Publication Date: Dec 2018

Publication Type(s): Journal Article

PubMedID: 30520828

Abstract:BACKGROUND: A sensitive, robust method was developed and validated to quantitate thirteen major natural cannabinoid parent and metabolite compounds in human plasma at or below 0.5 ng/mL.METHODS: A liquid chromatography-tandem mass spectrometry method was developed and validated to measure thirteen cannabinoid compounds: cannabidiol (CBD), cannabidiolic acid (CBDA), cannabidivarin (CBDV), cannabinol (CBN), cannabigerol (CBG), cannabigerolic acid (CBGA), cannabichromene (CBC), Δ-tetrahydocannabinol (THC), Δ-tetrahydrocannabinolic acid A (THCA), Δ-tetrahydrocannabivarin (THCV), 11-hydroxy-Δ-tetrahydrocannbinol (11-OH-THC), 11-nor-9-carboxy-Δ-tetrahydrocannbinol (THC-COOH), and 11-nor-9-carboxy-Δ-tetrahydrocannabinol-glucuronide (THC-COOH-glu). Samples (200 µL) were extracted via protein precipitation and separated with a Kinetex-EVO C18 column and a 65%-95% gradient of methanol and 0.2% ammonium hydroxide/H2O at a flow rate of 0.4 mL/min. Samples were obtained from patients with epilepsy receiving cannabis for the treatment of seizures.RESULTS: The extracted lower limit of quantification was 0.05 ng/mL for CBD, CBDV, CBN, and 11-OH-THC; 0.10 ng/mL for CBDA, CBG, CBC, CBGA, THC, THCA, and THCV; 0.50 ng/mL for THC-COOH and THC-COOH-glu. Mean QC intra-day accuracy and precision for all analytes ranged 96.5-104% and 2.7-4.9% respectively while inter-day accuracy and precision ranged 98-103.3% and 0.2-3.6%, respectively. An absolute matrix effect was observed for some analytes, however, with minimal relative matrix effect. Lack of nonspecific drug binding to extraction glass and plasticware was verified. Patient CBD levels ranged from 0.135-11.13 ng/mL.CONCLUSIONS: The validated method met FDA guidelines for Bioanalytical Assays precision and accuracy criteria. The assay reliably confirmed the use of particular medical cannabis formulations in patient samples as well as reliably measured low CBD concentrations from single dose CBD exposure.

Database: PubMed

8. Cannabis-based products for pediatric epilepsy: A systematic review.

Author(s): Elliott J; DeJean D; Clifford T; Coyle D; Potter BK; Skidmore B; Alexander C; Repetski AE; Shukla V; McCoy B; Wells GA

Source: Epilepsia; Jan 2019; vol. 60 (no. 1); p. 6-19

Publication Date: Jan 2019

Publication Type(s): Journal Article

PubMedID: 30515765

Available  at Epilepsia –  from Wiley

Available  at Epilepsia –  from IngentaConnect

Abstract:OBJECTIVE: To assess the benefits and harms of cannabis-based products for pediatric epilepsy.METHODS: We identified in this living systematic review randomized controlled trials (RCTs) and nonrandomized studies (NRSs) involving children with epilepsy treated with cannabis-based products. We searched MEDLINE, Embase, PsycINFO, Cochrane Library, and gray literature (April 25, 2018). The primary outcome was seizure freedom; secondary outcomes were seizure frequency (total, ≥50% reduction), quality of life, sleep, status epilepticus, death, gastrointestinal adverse events, and visits to the emergency room. Data were pooled by random-effects meta-analysis. Risk of bias was assessed for each study, and GRADE was used to assess the quality of evidence for each outcome.RESULTS: Four RCTs and 19 NRSs were included, primarily involving cannabidiol. All RCTs were at low risk of bias, whereas all NRSs were at high risk. Among RCTs, there was no statistically significant difference between cannabidiol and placebo in seizure freedom (relative risk [RR] = 6.77, 95% confidence interval [CI] = 0.36-128.38; 1 RCT), quality of life (mean difference = 0.6, 95% CI = -2.6 to 3.9; 3 RCTs), sleep disruption (mean difference = -0.3, 95% CI = -0.8 to 0.2; 3 RCTs), or vomiting (RR = 1.00, 95% CI = 0.51-1.96; 4 RCTs). There was a statistically significant reduction in the median frequency of monthly seizures with cannabidiol compared with placebo (-19.8%, 95% CI = -27.0% to -12.6%; 3 RCTs) and an increase in the number of participants with at least a 50% reduction in seizures (RR = 1.76, 95% CI = 1.07-2.88; 1 RCT) and diarrhea (RR = 2.25, 95% CI = 1.38-3.68; 3 RCTs). Death and status epilepticus were infrequently reported.SIGNIFICANCE: Evidence from high-quality RCTs suggests that cannabidiol probably reduces seizures among children with drug-resistant epilepsy (moderate certainty). At this time, the evidence base is primarily limited to cannabidiol, and these findings should not be extended to all cannabis-based products.

Database: PubMed

9. Emerging drugs for the treatment of Dravet syndrome.

Author(s): Brigo F; Striano P; Balagura G; Belcastro V

Source: Expert opinion on emerging drugs; Nov 2018

Publication Date: Nov 2018

Publication Type(s): Journal Article

PubMedID: 30482063

Abstract:INTRODUCTION: Dravet syndrome (DS) is an early-onset genetic developmental epileptic encephalopathy characterized by multiple seizure types which are refractory to antiseizure medication. There is an unmet need for effective and tolerable drugs to control different seizure types in DS types, with the aim of improving quality of life and preventing neurological impairment. Areas covered: Narrative review of efficacy and tolerability of fenfluramine, cannabidiol (CBD), verapamil and modulators of serotonin signaling pathways (lorcaserin or trazodone) in the treatment of DS. Expert Opinion/Commentary: A recent large randomized controlled-trial has shown that CBD is effective in the treatment of DS; preliminary data from the placebo-controlled trial on fenfluramine are also promising. Further studies are definitely required to evaluate the role of verapamil and modulators of serotonin signaling in DS. At present, drugs used to treat seizures in DS treat the symptoms of epilepsy rather than its cause(s). Future research should focus on elucidating the natural history of DS and whether appropriate treatment can have a beneficial impact on its disease course. A multidisciplinary, individualized approach to care of DS patients is required.

Database: PubMed

10. Long-Term Safety, Tolerability, and Efficacy of Cannabidiol in Children with Refractory Epilepsy: Results from an Expanded Access Program in the US.

Author(s): Sands TT; Rahdari S; Oldham MS; Caminha Nunes E; Tilton N; Cilio MR

Source: CNS drugs; Jan 2019; vol. 33 (no. 1); p. 47-60

Publication Date: Jan 2019

Publication Type(s): Journal Article

PubMedID: 30460546

Abstract:BACKGROUND: Purified cannabidiol is a new antiepileptic drug that has recently been approved for use in patients with Lennox-Gastaut and Dravet syndromes, but most published studies have not extended beyond 12-16 weeks.OBJECTIVE: The objective of this study was to evaluate the long-term safety, tolerability, and efficacy of cannabidiol in children with epilepsy.METHODS: Patients aged 1-17 years with refractory epilepsy were enrolled in an open-label prospective study through individual patient and expanded access programs between April 2013 and December 2014. Seizure types were video-electroencephalogram confirmed prior to enrollment. After a 28-day evaluation period, during which baseline seizure frequency was assessed, cannabidiol was given as add-on therapy at 5 mg/kg/day and titrated weekly by 5-mg/kg increments to a dose of 25 mg/kg/day. Blood tests were performed at baseline, after 1, 2, and 3 months, and every 3 months thereafter. Trough concentrations of concomitant antiepileptic drugs were measured at baseline, after 1, 2, and 3 months of therapy, and as clinically indicated afterwards. Concomitant antiepileptic drugs, ketogenic diet ratio, and vagal nerve stimulator settings remained unchanged during the baseline period and the first 3 months of treatment, unless there was a significant increase in plasma concentrations. Seizure frequency was reported daily in seizure diaries by parents or caregivers. Clinical assessments occurred after 15 days of treatment, at 1 month, at 3 months, and every 3 months thereafter. Diaries of seizure frequency and adverse events were reviewed at each visit. The primary efficacy outcome was a reduction in seizure frequency and responders were defined as those patients achieving a > 50% reduction in motor seizures.RESULTS: Twenty-six children were enrolled. Most had genetic epilepsies with daily or weekly seizures and multiple seizure types. All were refractory to prior antiepileptic drugs (range 4-11, mean 7), and were taking two antiepileptic drugs on average. Duration of therapy ranged from 4 to 53 months (mean 21 months). Adverse events were reported in 21 patients (80.8%), including reduced appetite in ten (38.4%), diarrhea in nine (34.6%), and weight loss in eight (30.7%). Four (15.4%) had changes in antiepileptic drug concentrations and three had elevated aspartate aminotransferase and alanine aminotransferase levels when cannabidiol was administered together with valproate. Serious adverse events, reported in six patients (23.1%), included status epilepticus in three, catatonia in two, and hypoalbuminemia in one. Fifteen patients (57.7%) discontinued cannabidiol for lack of efficacy, one because of status epilepticus, and one for severe weight loss. The retention rate declined rapidly in the first 6 months and more gradually thereafter. At 24 months, the number of patients continuing cannabidiol as adjunctive therapy was nine of the original 26 (34.6%). Of these patients, seven (26.9%) had a sustained > 50% reduction in motor seizures, including three (11.5%) who remain seizure free.CONCLUSION: Over a 4-year period, cannabidiol was effective in 26.9% of children with otherwise refractory epilepsy. It was well tolerated in about 20% of patients, but 80.8% had adverse events, including 23.1% with serious adverse events. Decreased appetite and diarrhea were frequent along with weight loss that became evident only later in the treatment.

Database: PubMed

11. Cannabis for the treatment of paediatric epilepsy? An update for Canadian paediatricians.

Author(s): James Huntsman R; Tang-Wai R; Acton B; Alcorn J; William Lyon A; David Mousseau D; Seifert B; Laprairie R; Prosser-Loose E; Ondrej Hanuš L

Source: Paediatrics & child health; Sep 2018; vol. 23 (no. 6); p. 368-373

Publication Date: Sep 2018

Publication Type(s): Journal Article

PubMedID: 30455572

Available  at Paediatrics & child health –  from ProQuest (Hospital Premium Collection) – NHS Version

Available  at Paediatrics & child health –  from Europe PubMed Central – Open Access

Abstract:The plant Cannabis sativa produces over 140 known cannabinoids. These chemicals generate considerable interest in the medical research community for their possible application to several intractable disease conditions. Recent reports have prompted parents to strongly consider Cannabis products to treat their children with drug resistant epilepsy. Physicians, though, are reluctant to prescribe Cannabis products due to confusion about their regulatory status and limited clinical data supporting their use. We provide the general paediatrician with a brief review of cannabinoid biology, the literature regarding their use in children with drug resistant epilepsy, the current Health Canada and Canadian Paediatric Society recommendations and also the regulations from the physician regulatory bodies for each province and territory. Given the complexities of conducting research on Cannabis products for children with epilepsy, we also discuss outstanding research objectives that must be addressed to support Cannabis products as an accepted treatment option for children with refractory epilepsy.

Database: PubMed

12. Epilepsy and Cannabis: A Literature Review.

Author(s): Zaheer S; Kumar D; Khan MT; Giyanwani PR; Kiran F

Source: Cureus; Sep 2018; vol. 10 (no. 9); p. e3278

Publication Date: Sep 2018

Publication Type(s): Journal Article; Review

PubMedID: 30443449

Available  at Cureus –  from Europe PubMed Central – Open Access

Abstract:Epilepsy is considered to be one of the most common non-communicable neurological diseases especially in low to middle-income countries. Approximately one-third of patients with epilepsy have seizures that are resistant to antiepileptic medications. Clinical trials for the treatment of medically refractory epilepsy have mostly focused on new drug treatments, and result in a significant portion of subjects whose seizures remain refractory to medication. The off-label use of cannabis sativa plant in treating seizures is known since ancient times. The active ingredients of this plant are delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), the latter considered safer and more effective in treating seizures, and with less adverse psychotropic effects. Clinical trials prior to two years ago have shown little to no significant effects of cannabis in reducing seizures. These trials seem to be underpowered, with a sample size less than 15. In contrast, more recent studies that have included over 100 participants showed that CBD use resulted in a significant reduction in seizure frequency. Adverse effects of CBD overall appear to be benign, while more concerning adverse effects (e.g., elevated liver enzymes) improve with continued CBD use or dose reduction. In most of the trials, CBD is used in adjunct with epilepsy medication, therefore it remains to be determined whether CBD is itself antiepileptic or a potentiator of traditional antiepileptic medications. Future trials may evaluate the efficacy of CBD in treating seizures due to specific etiologies (e.g., post-traumatic, post-stroke, idiopathic).

Database: PubMed

13. The Endocannabinoid System and Oligodendrocytes in Health and Disease.

Author(s): Ilyasov AA; Milligan CE; Pharr EP; Howlett AC

Source: Frontiers in neuroscience; 2018; vol. 12 ; p. 733

Publication Date: 2018

Publication Type(s): Journal Article; Review

PubMedID: 30416422

Available  at Frontiers in neuroscience –  from Europe PubMed Central – Open Access

Abstract:Cannabinoid-based interventions are being explored for central nervous system (CNS) pathologies such as neurodegeneration, demyelination, epilepsy, stroke, and trauma. As these disease states involve dysregulation of myelin integrity and/or remyelination, it is important to consider effects of the endocannabinoid system on oligodendrocytes and their precursors. In this review, we examine research reports on the effects of the endocannabinoid system (ECS) components on oligodendrocytes and their precursors, with a focus on therapeutic implications. Cannabinoid ligands and modulators of the endocannabinoid system promote cell signaling in oligodendrocyte precursor survival, proliferation, migration and differentiation, and mature oligodendrocyte survival and myelination. Agonist stimulation of oligodendrocyte precursor cells (OPCs) at both CB1 and CB2 receptors counter apoptotic processes via Akt/PI3K, and promote proliferation via Akt/mTOR and ERK pathways. CB1 receptors in radial glia promote proliferation and conversion to progenitors fated to become oligodendroglia, whereas CB2 receptors promote OPC migration in neonatal development. OPCs produce 2-arachidonoylglycerol (2-AG), stimulating cannabinoid receptor-mediated ERK pathways responsible for differentiation to arborized, myelin basic protein (MBP)-producing oligodendrocytes. In cell culture models of excitotoxicity, increased reactive oxygen species, and depolarization-dependent calcium influx, CB1 agonists improved viability of oligodendrocytes. In transient and permanent middle cerebral artery occlusion models of anoxic stroke, WIN55212-2 increased OPC proliferation and maturation to oligodendroglia, thereby reducing cerebral tissue damage. In several models of rodent encephalomyelitis, chronic treatment with cannabinoid agonists ameliorated the damage by promoting OPC survival and oligodendrocyte function. Pharmacotherapeutic strategies based upon ECS and oligodendrocyte production and survival should be considered.

Database: PubMed

14. Cannabis Therapeutics and the Future of Neurology.

Author(s): Russo EB

Source: Frontiers in integrative neuroscience; 2018; vol. 12 ; p. 51

Publication Date: 2018

Publication Type(s): Journal Article

PubMedID: 30405366

Available  at Frontiers in integrative neuroscience –  from Europe PubMed Central – Open Access

Abstract:Neurological therapeutics have been hampered by its inability to advance beyond symptomatic treatment of neurodegenerative disorders into the realm of actual palliation, arrest or reversal of the attendant pathological processes. While cannabis-based medicines have demonstrated safety, efficacy and consistency sufficient for regulatory approval in spasticity in multiple sclerosis (MS), and in Dravet and Lennox-Gastaut Syndromes (LGS), many therapeutic challenges remain. This review will examine the intriguing promise that recent discoveries regarding cannabis-based medicines offer to neurological therapeutics by incorporating the neutral phytocannabinoids tetrahydrocannabinol (THC), cannabidiol (CBD), their acidic precursors, tetrahydrocannabinolic acid (THCA) and cannabidiolic acid (CBDA), and cannabis terpenoids in the putative treatment of five syndromes, currently labeled recalcitrant to therapeutic success, and wherein improved pharmacological intervention is required: intractable epilepsy, brain tumors, Parkinson disease (PD), Alzheimer disease (AD) and traumatic brain injury (TBI)/chronic traumatic encephalopathy (CTE). Current basic science and clinical investigations support the safety and efficacy of such interventions in treatment of these currently intractable conditions, that in some cases share pathological processes, and the plausibility of interventions that harness endocannabinoid mechanisms, whether mediated via direct activity on CB1 and CB2 (tetrahydrocannabinol, THC, caryophyllene), peroxisome proliferator-activated receptor-gamma (PPARγ; THCA), 5-HT1A (CBD, CBDA) or even nutritional approaches utilizing prebiotics and probiotics. The inherent polypharmaceutical properties of cannabis botanicals offer distinct advantages over the current single-target pharmaceutical model and portend to revolutionize neurological treatment into a new reality of effective interventional and even preventative treatment.

Database: PubMed

15. Efficacy of cannabinoids in paediatric epilepsy.

Author(s): Ali S; Scheffer IE; Sadleir LG

Source: Developmental medicine and child neurology; 2019; vol. 61 (no. 1); p. 13-18

Publication Date: 2019

Publication Type(s): Journal Article; Review

PubMedID: 30402932

Available  at Developmental medicine and child neurology –  from Wiley

Abstract:There are hundreds of compounds found in the marijuana plant, each contributing differently to the antiepileptic and psychiatric effects. Cannabidiol (CBD) has the most evidence of antiepileptic efficacy and does not have the psychoactive effects of ∆9 -tetrahydrocannabinol. CBD does not act via cannabinoid receptors and its antiepileptic mechanism of action is unknown. Despite considerable community interest in the use of CBD for paediatric epilepsy, there has been little evidence for its use apart from anecdotal reports, until the last year. Three randomized, placebo-controlled, double-blind trials in Dravet syndrome and Lennox-Gastaut syndrome found that CBD produced a 38% to 41% median reduction in all seizures compared to 13% to 19% on placebo. Similarly, CBD resulted in a 39% to 46% responder rate (50% convulsive or drop-seizure reduction) compared to 14% to 27% on placebo. CBD was well tolerated; however, sedation, diarrhoea, and decreased appetite were frequent. CBD shows similar efficacy to established antiepileptic drugs. WHAT THIS PAPER ADDS: Cannabidiol (CBD) shows similar efficacy in the severe paediatric epilepsies to other antiepileptic drugs. Careful down-titration of benzodiazepines is essential to minimize sedation with adjunctive CBD.

Database: PubMed

16. Medical cannabis: A needs analysis for people with epilepsy.

Author(s): Kerai A; Sim TF; Emmerton L

Source: Complementary therapies in clinical practice; Nov 2018; vol. 33 ; p. 43-48

Publication Date: Nov 2018

Publication Type(s): Journal Article

PubMedID: 30396625

Available  at Complementary therapies in clinical practice –  from ClinicalKey

Abstract:BACKGROUND AND PURPOSE: Medical cannabis may be effective treatment for refractory epilepsy. It is timely to seek users’ and potential users’ opinions in regard to its place in the management of epilepsy.MATERIALS AND METHODS: An online survey was administered to members of an epilepsy support organisation in Western Australia. Experience with cannabis for management of epilepsy was explored, along with desire to trial a particular pharmaceutical formulation(s).RESULTS: People with epilepsy (33/71) and carers (38/71) participated. Fifty-four participants indicated no experience with medical cannabis, although 35, mainly with inadequate response to prescription medicines, were willing to ask for a prescription. Concerns included difficulty accessing cannabis and high cost of this treatment. Tablets/capsules was the most acceptable dosage form for development.CONCLUSION: These findings suggest wide interest in trialling medical cannabis in individual cases of refractory epilepsy, despite the developing body of literature and some concerns about cost and procurement.

Database: PubMed

17. Efficacy and Safety of Cannabidiol in Epilepsy: A Systematic Review and Meta-Analysis.

Author(s): Lattanzi S; Brigo F; Trinka E; Zaccara G; Cagnetti C; Del Giovane C; Silvestrini M

Source: Drugs; Nov 2018; vol. 78 (no. 17); p. 1791-1804

Publication Date: Nov 2018

Publication Type(s): Journal Article; Review

PubMedID: 30390221

Abstract:BACKGROUND: Approximately one-third of patients with epilepsy presents seizures despite adequate treatment. Hence, there is the need to search for new therapeutic options. Cannabidiol (CBD) is a major chemical component of the resin of Cannabis sativa plant, most commonly known as marijuana. The anti-seizure properties of CBD do not relate to the direct action on cannabinoid receptors, but are mediated by a multitude of mechanisms that include the agonist and antagonist effects on ionic channels, neurotransmitter transporters, and multiple 7-transmembrane receptors. In contrast to tetra-hydrocannabinol, CBD lacks psychoactive properties, does not produce euphoric or intrusive side effects, and is largely devoid of abuse liability.OBJECTIVE: The aim of the study was to estimate the efficacy and safety of CBD as adjunctive treatment in patients with epilepsy using meta-analytical techniques.METHODS: Randomized, placebo-controlled, single- or double-blinded add-on trials of oral CBD in patients with uncontrolled epilepsy were identified. Main outcomes included the percentage change and the proportion of patients with ≥ 50% reduction in monthly seizure frequency during the treatment period and the incidence of treatment withdrawal and adverse events (AEs).RESULTS: Four trials involving 550 patients with Lennox-Gastaut syndrome (LGS) and Dravet syndrome (DS) were included. The pooled average difference in change in seizure frequency during the treatment period resulted 19.5 [95% confidence interval (CI) 8.1-31.0; p = 0.001] percentage points between the CBD 10 mg and placebo groups and 19.9 (95% CI 11.8-28.1; p < 0.001) percentage points between the CBD 20 mg and placebo arms, in favor of CBD. The reduction in all-types seizure frequency by at least 50% occurred in 37.2% of the patients in the CBD 20 mg group and 21.2% of the placebo-treated participants [risk ratio (RR) 1.76, 95% CI 1.07-2.88; p = 0.025]. Across the trials, drug withdrawal for any reason occurred in 11.1% and 2.6% of participants receiving CBD and placebo, respectively (RR 3.54, 95% CI 1.55-8.12; p = 0.003) [Chi squared = 2.53, degrees of freedom (df) = 3, p = 0.506; I2 = 0.0%]. The RRs to discontinue treatment were 1.45 (95% CI 0.28-7.41; p = 0.657) and 4.20 (95% CI 1.82-9.68; p = 0.001) for CBD at the doses of 10 and 20 mg/kg/day, respectively, in comparison to placebo. Treatment was discontinued due to AEs in 8.9% and 1.8% of patients in the active and control arms, respectively (RR 5.59, 95% CI 1.87-16.73; p = 0.002). The corresponding RRs for CBD at the doses of 10 and 20 mg/kg/day were 1.66 (95% CI 0.22-12.86; p = 0.626) and 6.89 (95% CI 2.28-20.80; p = 0.001). AEs occurred in 87.9% and 72.2% of patients treated with CBD and placebo (RR 1.22, 95% CI 1.11-1.33; p < 0.001). AEs significantly associated with CBD were somnolence, decreased appetite, diarrhea, and increased serum aminotransferases.CONCLUSIONS: Adjunctive CBD in patients with LGS or DS experiencing seizures uncontrolled by concomitant anti-epileptic treatment regimens is associated with a greater reduction in seizure frequency and a higher rate of AEs than placebo.

Database: PubMed

18. Cannabis and epilepsy.

Author(s): Thomas RH; Cunningham MO

Source: Practical neurology; Dec 2018; vol. 18 (no. 6); p. 465-471

Publication Date: Dec 2018

Publication Type(s): Journal Article; Review

PubMedID: 30337476

Available  at Practical neurology –  from BMJ Journals – NHS

Abstract:Click here to listen to the Podcast The one-third of people who do not gain seizure control through current treatment options need a revolution in epilepsy therapeutics. The general population appears to be showing a fundamental and rapid shift in its opinion regarding cannabis and cannabis-related drugs. It is quite possible that cannabidiol, licensed in the USA for treating rare genetic epilepsies, may open the door for the widespread legalisation of recreational cannabis. It is important that neurologists understand the difference between artisanal cannabidiol products available legally on the high street and the cannabidiol medications that have strong trial evidence. In the UK in 2018 there are multiple high-profile reports of the response of children taking cannabis-derived medication, meaning that neurologists are commonly asked questions about these treatments in clinic. We address what an adult neurologist needs to know now, ahead of the likely licensing of Epidiolex in the UK in 2019.

Database: PubMed

19. Potential Clinical Benefits of CBD-Rich Cannabis Extracts Over Purified CBD in Treatment-Resistant Epilepsy: Observational Data Meta-analysis.

Author(s): Pamplona FA; da Silva LR; Coan AC

Source: Frontiers in neurology; 2018; vol. 9 ; p. 759

Publication Date: 2018

Publication Type(s): Journal Article

PubMedID: 30258398

Available  at Frontiers in neurology –  from Europe PubMed Central – Open Access

Abstract:This meta-analysis paper describes the analysis of observational clinical studies on the treatment of refractory epilepsy with cannabidiol (CBD)-based products. Beyond attempting to establish the safety and efficacy of such products, we also investigated if there is enough evidence to assume any difference in efficacy between CBD-rich extracts compared to purified CBD products. The systematic search took place in February/2017 and updated in December/2017 using the keywords “epilepsy” or “Dravet” or “Lennox-Gastaut” or “CDKL5” combined with “Cannabis,” “cannabinoid,” “cannabidiol,” or “CBD” resulting in 199 papers. The qualitative assessment resulted in 11 valid references, with an average impact factor of 8.1 (ranging from 1.4 to 47.8). The categorical data of a total of 670 patients were analyzed by Fischer test. The average daily dose ranged between 1 and 50 mg/kg, with treatment length from 3 to 12 months (mean 6.2 months). Two thirds of patients reported improvement in the frequency of seizures (399/622, 64%). There were more reports of improvement from patients treated with CBD-rich extracts (318/447, 71%) than patients treated with purified CBD (81/223, 36%), with statistical significance (p < 0.0001). Nevertheless, when the standard clinical threshold of a “50% reduction or more in the frequency of seizures” was applied, only 39% of the individuals were considered “responders,” and there was no difference (p = 0.56) between treatments with CBD-rich extracts (97/255, 38%) and purified CBD (94/223, 42%). Patients treated with CBD-rich extracts reported lower average dose (6.1 mg/kg/day) than those using purified CBD (27.1 mg/kg/day). The reports of mild (109/285 vs. 291/346, p < 0.0001) and severe (23/285 vs. 77/346, p < 0.0001) adverse effects were more frequent in products containing purified CBD than in CBD-rich extracts. CBD-rich extracts seem to present a better therapeutic profile than purified CBD, at least in this population of patients with refractory epilepsy. The roots of this difference is likely due to synergistic effects of CBD with other phytocompounds (aka Entourage effect), but this remains to be confirmed in controlled clinical studies.

Database: PubMed

20. Cannabidiol for Treatment of Childhood Epilepsy-A Cross-Sectional Survey.

Author(s): Klotz KA; Schulze-Bonhage A; Antonio-Arce VS; Jacobs J

Source: Frontiers in neurology; 2018; vol. 9 ; p. 731

Publication Date: 2018

Publication Type(s): Journal Article

PubMedID: 30258395

Available  at Frontiers in neurology –  from Europe PubMed Central – Open Access

Abstract:Background: The interest in cannabidiol (CBD) for treatment of epilepsy has been increasing over the last years. However, practitioner’s attitudes concerning the use of CBD for epilepsy treatment appears to be divided and data about its clinical use in daily practice are not available. Objective: To improve the knowledge about the current use of CBD amongst European practitioners treating children and adolescents for epilepsy. Methods: Cross-sectional survey using an open-access online questionnaire for physicians treating children or adolescents for epilepsy within eight European countries from December 2017 to March 2018. Results: One-hundred fifty-five physicians participated in the survey. CBD is increasingly used by 45% (69/155) of participants, treating a mean (range) number of 3 (1-35) with CBD. Only 48% of the participants prescribing CBD are exclusively using purified CBD to treat children and adolescents with epilepsy, the remainder also applies preparations containing delta9-tetrahydrocannabinol (THC). Reported daily CBD doses range from < 10 to 50 mg/kg body weight. Management of CBD therapy in regard of monitoring side effects and adjusting concomitant therapy differs widely amongst participants. Their primary objective for commencing CBD is improving patient’s quality of life. Participants frequently receive inquiries about CBD treatment but only 40% may actively suggest CBD as a treatment option. Of the 85 participants currently not using CBD for epilepsy treatment, 70% would consider using CBD if available in their country of practice or given the opportunity to become familiar with this treatment option. Conclusions: CBD is increasingly used by participating physicians but individual experience remains limited. There are very diverse opinions about the use of CBD to treat epilepsy in children and adolescents and widely differing views on how to manage the CBD treatment.

Database: PubMed

21. A prospective open-label trial of a CBD/THC cannabis oil in dravet syndrome.

Author(s): McCoy B; Wang L; Zak M; Al-Mehmadi S; Kabir N; Alhadid K; McDonald K; Zhang G; Sharma R; Whitney R; Sinopoli K; Snead OC

Source: Annals of clinical and translational neurology; Sep 2018; vol. 5 (no. 9); p. 1077-1088

Publication Date: Sep 2018

Publication Type(s): Journal Article

PubMedID: 30250864

Available  at Annals of clinical and translational neurology –  from Europe PubMed Central – Open Access

Abstract:Introduction: Both Δ9 Tetrahydrocannabidiol (THC) and cannabidiol (CBD) components of cannabis, have been shown to have anticonvulsant effects. Cannabis oils are used to treat seizures in drug-resistant epilepsy (DRE). Recent trials provide data on dosing, side effects, and efficacy of CBD, yet there is a paucity of information on THC in epilepsy. Primary objective was to establish dosing and tolerability of TIL-TC150 – a cannabis plant extract produced by Tilray®, containing 100 mg/mL CBD and 2 mg/mL THC- in children with Dravet syndrome. Secondary objectives were to assess impact of therapy on seizures, electroencephalogram (EEG) and quality of life.Methods: Twenty children received add-on therapy with TIL-TC150. The dose ranged from 2 to 16 mg/kg/day of CBD and 0.04 to 0.32 mg/kg/day of THC. Patients were monitored for tolerability and adverse events, and secondary objectives.Results: Nineteen participants completed the 20-week intervention. Mean dose achieved was 13.3 mg/kg/day of CBD (range 7-16 mg/kg/day) and 0.27 mg/kg/day of THC (range 0.14-0.32 mg/kg/day). Adverse events, common during titration included somnolence, anorexia, and diarrhea. Abnormalities of liver transaminases and platelets were observed with concomitant valproic acid therapy. There was a statistically significant improvement in quality of life, reduction in EEG spike activity, and median motor seizure reduction of 70.6%, with 50% responder rate of 63%.Conclusions: TIL-TC150 was safe and well tolerated in our subjects. TIL-TC150 treatment resulted in a reduction in seizure counts, spike index on EEG, and improved quality of life measures. This study provides safety and dosing information for THC-containing cannabinoid preparations.

Database: PubMed

22. Inhibitory effects of cannabidiol on voltage-dependent sodium currents.

Author(s): Ghovanloo MR; Shuart NG; Mezeyova J; Dean RA; Ruben PC; Goodchild SJ

Source: The Journal of biological chemistry; Oct 2018; vol. 293 (no. 43); p. 16546-16558

Publication Date: Oct 2018

Publication Type(s): Journal Article

PubMedID: 30219789

Abstract:Cannabis sativa contains many related compounds known as phytocannabinoids. The main psychoactive and nonpsychoactive compounds are Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD), respectively. Much of the evidence for clinical efficacy of CBD-mediated antiepileptic effects has been from case reports or smaller surveys. The mechanisms for CBD’s anticonvulsant effects are unclear and likely involve noncannabinoid receptor pathways. CBD is reported to modulate several ion channels, including sodium channels (Nav). Evaluating the therapeutic mechanisms and safety of CBD demands a richer understanding of its interactions with central nervous system targets. Here, we used voltage-clamp electrophysiology of HEK-293 cells and iPSC neurons to characterize the effects of CBD on Nav channels. Our results show that CBD inhibits hNav1.1-1.7 currents, with an IC50 of 1.9-3.8 μm, suggesting that this inhibition could occur at therapeutically relevant concentrations. A steep Hill slope of ∼3 suggested multiple interactions of CBD with Nav channels. CBD exhibited resting-state blockade, became more potent at depolarized potentials, and also slowed recovery from inactivation, supporting the idea that CBD binding preferentially stabilizes inactivated Nav channel states. We also found that CBD inhibits other voltage-dependent currents from diverse channels, including bacterial homomeric Nav channel (NaChBac) and voltage-gated potassium channel subunit Kv2.1. Lastly, the CBD block of Nav was temperature-dependent, with potency increasing at lower temperatures. We conclude that CBD’s mode of action likely involves 1) compound partitioning in lipid membranes, which alters membrane fluidity affecting gating, and 2) undetermined direct interactions with sodium and potassium channels, whose combined effects are loss of channel excitability.

Database: PubMed

23. Cannabis for the Treatment of Epilepsy: an Update.

Author(s): Gaston TE; Szaflarski JP

Source: Current neurology and neuroscience reports; Sep 2018; vol. 18 (no. 11); p. 73

Publication Date: Sep 2018

Publication Type(s): Journal Article; Review

PubMedID: 30194563

Abstract:PURPOSE OF REVIEW: For millennia, there has been interest in the use of cannabis for the treatment of epilepsy. However, it is only recently that appropriately powered controlled studies have been completed. In this review, we present an update on the research investigating the use of cannabidiol (CBD), a non-psychoactive component of cannabis, in the treatment of epilepsy.RECENT FINDINGS: While the anticonvulsant mechanism of action of CBD has not been entirely elucidated, we discuss the most recent data available including its low affinity for the endocannabinoid receptors and possible indirect modulation of these receptors via blocking the breakdown of anandamide. Additional targets include activation of the transient receptor potential of vanilloid type-1 (TRPV1), antagonist action at GPR55, targeting of abnormal sodium channels, blocking of T-type calcium channels, modulation of adenosine receptors, modulation of voltage-dependent anion selective channel protein (VDAC1), and modulation of tumor necrosis factor alpha release. We also discuss the most recent studies on various artisanal CBD products conducted in patients with epilepsy in the USA and internationally. While a high percentage of patients in these studies reported improvement in seizures, these studies were either retrospective or conducted via survey. Dosage/preparation of CBD was either unknown or not controlled in the majority of these studies. Finally, we present data from both open-label expanded access programs (EAPs) and randomized placebo-controlled trials (RCTs) of a highly purified oral preparation of CBD, which was recently approved by the FDA in the treatment of epilepsy. In the EAPs, there was a significant improvement in seizure frequency seen in a large number of patients with various types of treatment-refractory epilepsy. The RCTs have shown significant seizure reduction compared to placebo in patients with Dravet syndrome and Lennox-Gastaut syndrome. Finally, we describe the available data on adverse effects and drug-drug interactions with highly purified CBD. While this product is overall well tolerated, the most common side effects are diarrhea and sedation, with sedation being much more common in patients taking concomitant clobazam. There was also an increased incidence of aspartate aminotransferase and alanine aminotransferase elevations while taking CBD, with many of the patients with these abnormalities also taking concomitant valproate. CBD has a clear interaction with clobazam, significantly increasing the levels of its active metabolite N-desmethylclobazam in several studies; this is felt to be due to CBD’s inhibition of CYP2C19. EAP data demonstrate other possible interactions with rufinamide, zonisamide, topiramate, and eslicarbazepine. Additionally, there is one case report demonstrating need for warfarin dose adjustment with concomitant CBD. Understanding of CBD’s efficacy and safety in the treatment of TRE has expanded significantly in the last few years. Future controlled studies of various ratios of CBD and THC are needed as there could be further therapeutic potential of these compounds for patients with epilepsy.

Database: PubMed

24. Anticonvulsant and Neuroprotective Effects of Cannabidiol During the Juvenile Period.

Author(s): Friedman LK; Wongvravit JP

Source: Journal of neuropathology and experimental neurology; Oct 2018; vol. 77 (no. 10); p. 904-919

Publication Date: Oct 2018

Publication Type(s): Journal Article

PubMedID: 30169677

Abstract:Anticonvulsant effects of cannabidiol (CBD), a nonpsychoactive cannabinoid, have not been investigated in the juvenile brain. We hypothesized that CBD would attenuate epileptiform activity at an age when the brain first becomes vulnerable to neurotoxicity and social/cognitive impairments. To induce seizures, kainic acid (KA) was injected either into the hippocampus (KAih) or systemically (KAip) on postnatal (P) day 20. CBD was coadministered (KA + CBDih, KA + CBDip) or injected 30 minutes postseizure onset (KA/CBDih, KA/CBDip). Hyperactivity, clonic convulsions, and electroencephalogram rhythmic oscillations were attenuated or absent after KA + CBDih and reduced after KA + CBDip. NeuN immunohistochemistry revealed neuroprotection. Augmented reactive glia number and expression were reversed in CA1 but persisted deep within the dentate hilus. Parvalbumin-positive (PV+) interneurons were reduced in both models, whereas immunolabeling was dramatically increased within ipsilateral and contralateral dendritic/neuropilar fields following KA + CBDih. Cannabinoid receptor 1 (CB1) expression was minimally affected after KAih contrasting elevations observed after KAip. Intracranial coadministration data suggest that CBD has higher efficacy in epilepsy with hippocampal focus rather than when extrahippocampal amygdala/cortical structures are triggered by systemic treatments. Inhibition of surviving PV+ and CB1+ interneurons may be facilitated by CBD implying a protective role in regulating hippocampal seizures and neurotoxicity at juvenile ages.

Database: PubMed

25. Cannabidiol for Epilepsy: New Hope on the Horizon?

Author(s): Sanmartin PE; Detyniecki K

Source: Clinical therapeutics; Sep 2018; vol. 40 (no. 9); p. 1438-1441

Publication Date: Sep 2018

Publication Type(s): Journal Article; Review

PubMedID: 30150078

Available  at Clinical therapeutics –  from ClinicalKey

Available  at Clinical therapeutics –  from ProQuest (Hospital Premium Collection) – NHS Version

Abstract:Epilepsy is a common neurologic disorder; it is estimated that ∼50million people are affected worldwide. About one third of those patients are drug resistant, defined as failure to stop all seizures despite adequate trials of at least 2 appropriate medications. There has been an enormous interest in developing antiepileptic drugs with novel mechanisms of action. This review discusses the evidence supporting the anticonvulsant properties of cannabis in humans, focusing on cannabidiol. We begin by exploring the early and somewhat anecdotal evidence that was recently replaced by high-quality data from randomized controlled studies, which subsequently led to the US Food and Drug Administration approval of a purified cannabidiol extract for the treatment of 2 highly refractory pediatric epilepsy syndromes (Dravet and Lennox-Gastaut).

Database: PubMed

26. Cannabinoid signalling in the immature brain: Encephalopathies and neurodevelopmental disorders.

Author(s): Sagredo O; Palazuelos J; Gutierrez-Rodriguez A; Satta V; Galve-Roperh I; Martínez-Orgado J

Source: Biochemical pharmacology; Nov 2018; vol. 157 ; p. 85-96

Publication Date: Nov 2018

Publication Type(s): Journal Article; Review

PubMedID: 30118663

Abstract:The endocannabinoid system exerts a crucial neuromodulatory role in many brain areas that is essential for proper regulation of neuronal activity. The role of cannabinoid signalling controlling neuronal activity in the adult brain is also evident when considering its contribution to adult brain insults or neurodegenerative diseases. In the context of brain genetic or acquired encephalopathies administration of cannabinoid-based molecules has demonstrated to exert symptomatic relief and hence, they are proposed as new potential therapeutic compounds. This review article summarizes the main evidences indicating the beneficial action of cannabinoid-derived molecules in preclinical models of neonatal hypoxia/ischemic damage. In a second part, we discuss the available evidences of therapeutic actions of cannabidiol in children with refractory epilepsy syndromes. Finally, we discuss the current view of cannabinoid signalling mechanisms active in the immature brain that affect in neural cell fate and can contribute to long-term neural cell plasticity.

Database: PubMed

27. Cannabinoid-Based Therapies and Brain Development: Potential Harmful Effect of Early Modulation of the Endocannabinoid System.

Author(s): Schonhofen P; Bristot IJ; Crippa JA; Hallak JEC; Zuardi AW; Parsons RB; Klamt F

Source: CNS drugs; Aug 2018; vol. 32 (no. 8); p. 697-712

Publication Date: Aug 2018

Publication Type(s): Journal Article

PubMedID: 30109642

Abstract:The endocannabinoid retrograde signaling pathway is widely expressed in the central nervous system, where it plays major roles in regulating synaptic plasticity (excitatory and inhibitory) through long-term potentiation and long-term depression. The endocannabinoid system (ECS) components-cannabinoid receptors, endocannabinoids and synthesis/degradation enzymes-are expressed and are functional from early developmental stages and throughout adolescent cortical development, regulating progenitor cell fate, neural differentiation, migration and survival. This may potentially confer increased vulnerability to adverse outcomes from early cannabinoid exposure. Cannabidiol (CBD) is one of the most studied exogenous cannabinoids, and CBD-enriched Cannabis extracts have been widely (and successfully) used as adjuvants to treat children with refractory epilepsy, and there is even a Food and Drug Administration (FDA)-approved drug with purified CBD derived from Cannabis. However, there is insufficient information on possible long-term changes in the central nervous system caused by cannabinoid treatments during early childhood. Like the majority of cannabinoids, CBD is able to exert its effects directly and indirectly through the ECS, which can perturb the regulatory processes mediated by this system. In addition, CBD has a large number of non-endocannabinoid targets, which can explain CBD’s effects. Here, we review the current knowledge about CBD-based therapies-pure and CBD-enriched Cannabis extracts-in studies with pediatric patients, their side effects, and their mechanisms of action regarding the central nervous system and neurodevelopment aspects. Since Cannabis extracts contain Δ9-tetrahydrocannabinol (Δ9-THC), we consider that pure CBD is possibly safer for young patients. Nevertheless, CBD, as well as other natural and/or synthetic cannabinoids, should be studied in more detail as a therapeutic alternative to CBD-enriched Cannabis extracts for young patients.

Database: PubMed

28. Cannabidiol improves frequency and severity of seizures and reduces adverse events in an open-label add-on prospective study.

Author(s): Szaflarski JP; Bebin EM; Cutter G; DeWolfe J; Dure LS; Gaston TE; Kankirawatana P; Liu Y; Singh R; Standaert DG; Thomas AE; Ver Hoef LW; UAB CBD Program

Source: Epilepsy & behavior : E&B; Aug 2018

Publication Date: Aug 2018

Publication Type(s): Journal Article

PubMedID: 30100226

Available  at Epilepsy & behavior : E&B –  from ClinicalKey

Abstract:The objective of this study was to characterize the changes in adverse events, seizure severity, and frequency in response to a pharmaceutical formulation of highly purified cannabidiol (CBD; Epidiolex®) in a large, prospective, single-center, open-label study. We initiated CBD in 72 children and 60 adults with treatment-resistant epilepsy (TRE) at 5 mg/kg/day and titrated it up to a maximum dosage of 50 mg/kg/day. At each visit, we monitored treatment adverse events with the adverse events profile (AEP), seizure severity using the Chalfont Seizure Severity Scale (CSSS), and seizure frequency (SF) using seizure calendars. We analyzed data for the enrollment and visits at 12, 24, and 48 weeks. We recorded AEP, CSSS, and SF at each follow-up visit for the weeks preceding the visit (seizures were averaged over 2-week periods). Of the 139 study participants in this ongoing study, at the time of analysis, 132 had 12-week, 88 had 24-week, and 61 had 48-week data. Study retention was 77% at one year. There were no significant differences between participants who contributed all 4 data points and those who contributed 2 or 3 data points in baseline demographic and AEP/SF/CSSS measures. For all participants, AEP decreased between CBD initiation and the 12-week visit (40.8 vs. 33.2; p < 0.0001) with stable AEP scores thereafter (all p ≥ 0.14). Chalfont Seizure Severity Scale scores were 80.7 at baseline, decreasing to 39.2 at 12 weeks (p < 0.0001) and stable CSSS thereafter (all p ≥ 0.19). Bi-weekly SF decreased from a mean of 144.4 at entry to 52.2 at 12 weeks (p = 0.01) and remained stable thereafter (all p ≥ 0.65). Analyses of the pediatric and adult subgroups revealed similar patterns. Most patients were treated with dosages of CBD between 20 and 30 mg/kg/day. For the first time, this prospective, open-label safety study of CBD in TRE provides evidence for significant improvements in AEP, CSSS, and SF at 12 weeks that are sustained over the 48-week duration of treatment.

Database: PubMed

29. Cannabidiol for treating drug-resistant epilepsy in children: the New South Wales experience.

Author(s): Chen KA; Farrar M; Cardamone M; Gill D; Smith R; Cowell CT; Truong L; Lawson JA

Source: The Medical journal of Australia; Aug 2018; vol. 209 (no. 5); p. 217-221

Publication Date: Aug 2018

Publication Type(s): Journal Article

PubMedID: 30092753

Available  at The Medical journal of Australia –  from University Hospitals of Derby and Burton NHS Foundation Trust Local Print Collection Print Holdings: Latest Five years.[location] : RDH,Derby Hospitals NHS Foundation Trust., [location] : Print Holdings Latest Five years.  RDH,Derby Hospitals NHS Foundation Trust.

Abstract:OBJECTIVE: To evaluate the tolerability and safety of cannabidiol for treating drug-resistant epilepsy in children, and to describe adverse events associated with such treatment.STUDY DESIGN: Prospective, open label cohort study.SETTING: Three tertiary NSW referral centres with paediatric neurology services.PARTICIPANTS: First 40 children enrolled in the NSW Compassionate Access Scheme for children with drug-resistant epilepsy and uncountable daily seizures.INTERVENTION: Children received cannabidiol as an adjunct anti-epileptic drug, titrated to a maximum of 25 mg/kg/day, for up to 12 weeks.OUTCOME MEASURES: Adverse events, withdrawals, and caregiver and physician Global Impression of Change assessments were recorded at 4, 8 and 12 weeks. Seizure frequency could not be reliably recorded because of disease severity.RESULTS: Thirty-nine patients reported at least one adverse event; many were deemed unrelated to cannabidiol treatment. The most frequent treatment-related adverse event was somnolence (15 participants), which resolved spontaneously in ten patients; it was particularly frequent in patients taking higher clobazam doses. Gastrointestinal effects (nausea, vomiting, diarrhoea) were each reported by seven to nine participants. Four children were withdrawn from treatment, including one with elevated transaminase levels. The caregivers of 12 children felt the overall health of their children had much or very much improved; clinicians assessed seven children as being much or very much improved.CONCLUSION: Cannabidiol as an adjunct treatment had some subjective benefit for overall health, with a manageable adverse event profile. Monitoring changes in liver function and awareness of potential drug interactions is essential. Whether the reported benefit is attributable to cannabidiol cannot be established in an open label study of participants with severe intractable epilepsy.

Database: PubMed

30. Cannabis for pediatric epilepsy: protocol for a living systematic review.

Author(s): Elliott J; DeJean D; Clifford T; Coyle D; Potter B; Skidmore B; Alexander C; Repetski AE; McCoy B; Wells GA

Source: Systematic reviews; ; vol. 7 (no. 1); p. 95

Publication Type(s): Journal Article; Research Support, Non-U.S. Gov’t; Review

PubMedID: 30021618

Available  at Systematic reviews –  from ProQuest (Hospital Premium Collection) – NHS Version

Available  at Systematic reviews –  from BioMed Central

Available  at Systematic reviews –  from Europe PubMed Central – Open Access

Abstract:BACKGROUND: Pediatric epilepsy, including treatment-resistant forms, has a major effect on the quality of life, morbidity, and mortality of affected children. Interest has been growing in the use of medical cannabis as a treatment for pediatric epilepsy, yet there has been no comprehensive review of the benefits and harms of cannabis use in this population. In this systematic review, we will search for, synthesize, and assess the published and gray literature in order to provide usable and relevant information to parents, clinicians, and policy makers.METHODS: We will perform a living systematic review of studies involving the use of cannabis to treat pediatric epilepsy. We will search the published and gray literature for studies involving children with any type of epilepsy taking any form of cannabis. Studies will be selected for inclusion by two independent reviewers. The primary outcome is seizure freedom. Secondary outcomes are seizure frequency, quality of life (child, caregiver), quality and quantity of sleep, status epilepticus, tonic-clonic seizures, death (all-cause, sudden unexpected death in epilepsy), gastrointestinal adverse events (diarrhea, vomiting), and visits to the emergency room. The quality of each included study will be assessed. If data are sufficient in quantity and sufficiently similar, we will conduct pairwise random-effects meta-analysis. We will repeat the literature search every 6 months to identify studies published after the previous search date. Sequential meta-analysis will be performed as necessary to update the review findings.DISCUSSION: Our review aims to provide a comprehensive and up-to-date summary of the available evidence to inform decisions about the use of cannabis in children with treatment-resistant epilepsy. The results of this review will be of use to parents, clinicians, and policy makers as they navigate this rapidly evolving area.SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42018084755.

Database: PubMed

31. Open-label use of highly purified CBD (Epidiolex®) in patients with CDKL5 deficiency disorder and Aicardi, Dup15q, and Doose syndromes.

Author(s): Devinsky O; Verducci C; Thiele EA; Laux LC; Patel AD; Filloux F; Szaflarski JP; Wilfong A; Clark GD; Park YD; Seltzer LE; Bebin EM; Flamini R; Wechsler RT; Friedman D

Source: Epilepsy & behavior : E&B; Sep 2018; vol. 86 ; p. 131-137

Publication Date: Sep 2018

Publication Type(s): Journal Article

PubMedID: 30006259

Available  at Epilepsy & behavior : E&B –  from ClinicalKey

Abstract:OBJECTIVE: We studied our collective open-label, compassionate use experience in using cannabidiol (CBD) to treat epilepsy in patients with CDKL5 deficiency disorder and Aicardi, Doose, and Dup15q syndromes.METHODS: We included patients aged 1-30 years with severe childhood-onset epilepsy who received CBD for ≥10 weeks as part of multiple investigator-initiated expanded access or state access programs for a compassionate prospective interventional study: CDKL5 deficiency disorder (n = 20), Aicardi syndrome (n = 19), Dup15q syndrome (n = 8), and Doose syndrome (n = 8). These patients were treated at 11 institutions from January 2014 to December 2016.RESULTS: The percent change in median convulsive seizure frequency for all patients taking CBD in the efficacy group decreased from baseline [n = 46] to week 12 (51.4% [n = 35], interquartile range (IQR): 9-85%) and week 48 (59.1% [n = 27], IQR: 14-86%). There was a significant difference between the percent changes in monthly convulsive seizure frequency during baseline and week 12, χ2(2) = 22.9, p = 0.00001, with no difference in seizure percent change between weeks 12 and 48. Of the 55 patients in the safety group, 15 (27%) withdrew from extended observation by week 144: 4 due to adverse effects, 9 due to lack of efficacy, 1 withdrew consent, and 1 was lost to follow-up.SIGNIFICANCE: This open-label drug trial provides class III evidence for the long-term safety and efficacy of CBD administration in patients with treatment-resistant epilepsy (TRE) associated with CDKL5 deficiency disorder and Aicardi, Dup15q, and Doose syndromes. Adjuvant therapy with CBD showed similar safety and efficacy for these four syndromes as reported in a diverse population of TRE etiologies. This study extended analysis of the prior report from 12 weeks to 48 weeks of efficacy data and suggested that placebo-controlled randomized trials should be conducted to formally assess the safety and efficacy of CBD in these epileptic encephalopathies.

Database: PubMed

32. Long-term safety and treatment effects of cannabidiol in children and adults with treatment-resistant epilepsies: Expanded access program results.

Author(s): Szaflarski JP; Bebin EM; Comi AM; Patel AD; Joshi C; Checketts D; Beal JC; Laux LC; De Boer LM; Wong MH; Lopez M; Devinsky O; Lyons PD; Zentil PP; Wechsler R; CBD EAP study group

Source: Epilepsia; Aug 2018; vol. 59 (no. 8); p. 1540-1548

Publication Date: Aug 2018

Publication Type(s): Journal Article

PubMedID: 29998598

Available  at Epilepsia –  from Wiley

Available  at Epilepsia –  from IngentaConnect

Abstract:OBJECTIVE: Since 2014, cannabidiol (CBD) has been administered to patients with treatment-resistant epilepsies (TREs) in an ongoing expanded-access program (EAP). We report interim results on the safety and efficacy of CBD in EAP patients treated through December 2016.METHODS: Twenty-five US-based EAP sites enrolling patients with TRE taking stable doses of antiepileptic drugs (AEDs) at baseline were included. During the 4-week baseline period, parents/caregivers kept diaries of all countable seizure types. Patients received oral CBD starting at 2-10 mg/kg/d, titrated to a maximum dose of 25-50 mg/kg/d. Patient visits were every 2-4 weeks through 16 weeks and every 2-12 weeks thereafter. Efficacy endpoints included the percentage change from baseline in median monthly convulsive and total seizure frequency, and percentage of patients with ≥50%, ≥75%, and 100% reductions in seizures vs baseline. Data were analyzed descriptively for the efficacy analysis set and using the last-observation-carried-forward method to account for missing data. Adverse events (AEs) were documented at each visit.RESULTS: Of 607 patients in the safety dataset, 146 (24%) withdrew; the most common reasons were lack of efficacy (89 [15%]) and AEs (32 [5%]). Mean age was 13 years (range, 0.4-62). Median number of concomitant AEDs was 3 (range, 0-10). Median CBD dose was 25 mg/kg/d; median treatment duration was 48 weeks. Add-on CBD reduced median monthly convulsive seizures by 51% and total seizures by 48% at 12 weeks; reductions were similar through 96 weeks. Proportion of patients with ≥50%, ≥75%, and 100% reductions in convulsive seizures were 52%, 31%, and 11%, respectively, at 12 weeks, with similar rates through 96 weeks. CBD was generally well tolerated; most common AEs were diarrhea (29%) and somnolence (22%).SIGNIFICANCE: Results from this ongoing EAP support previous observational and clinical trial data showing that add-on CBD may be an efficacious long-term treatment option for TRE.

Database: PubMed

33. The protocol for the Cannabidiol in children with refractory epileptic encephalopathy (CARE-E) study: a phase 1 dosage escalation study.

Author(s): Reithmeier D; Tang-Wai R; Seifert B; Lyon AW; Alcorn J; Acton B; Corley S; Prosser-Loose E; Mousseau DD; Lim HJ; Tellez-Zenteno J; Huh L; Leung E; Carmant L; Huntsman RJ

Source: BMC pediatrics; Jul 2018; vol. 18 (no. 1); p. 221

Publication Date: Jul 2018

Publication Type(s): Journal Article

PubMedID: 29981580

Available  at BMC pediatrics –  from ProQuest (Hospital Premium Collection) – NHS Version

Available  at BMC pediatrics –  from BioMed Central

Available  at BMC pediatrics –  from Europe PubMed Central – Open Access

Available  at BMC pediatrics –  from EBSCO (MEDLINE Complete)

Abstract:BACKGROUND: Initial studies suggest pharmaceutical grade cannabidiol (CBD) can reduce the frequency of convulsive seizures and lead to improvements in quality of life in children affected by epileptic encephalopathies. With limited access to pharmaceutical CBD, Cannabis extracts in oil are becoming increasingly available. Physicians show reluctance to recommend Cannabis extracts given the lack of high quality safety data especially regarding the potential for harm caused by other cannabinoids, such as Δ9-tetrahydrocannabinol (Δ9-THC). The primary aims of the study presented in this protocol are (i) To determine whether CBD enriched Cannabis extract is safe and well-tolerated for pediatric patients with refractory epilepsy, (ii) To monitor the effects of CBD-enriched Cannabis extract on the frequency and duration of seizure types and on quality of life.METHODS: Twenty-eight children with treatment resistant epileptic encephalopathy ranging in age from 1 to 10 years will be recruited in four Canadian cities into an open-label, dose-escalation phase 1 trial. The primary objectives for the study are (i) To determine if the CBD-enriched Cannabis herbal extract is safe and well-tolerated for pediatric patients with treatment resistant epileptic encephalopathy and (ii) To determine the effect of CBD-enriched Cannabis herbal extract on the frequency and duration of seizures. Secondary objectives include (i) To determine if CBD-enriched Cannabis herbal extracts alter steady-state levels of co-administered anticonvulsant medications. (ii) To assess the relation between dose escalation and quality of life measures, (iii) To determine the relation between dose escalation and steady state trough levels of bioactive cannabinoids. (iv) To determine the relation between dose escalation and incidence of adverse effects.DISCUSSION: This paper describes the study design of a phase 1 trial of CBD-enriched Cannabis herbal extract in children with treatment-resistant epileptic encephalopathy. This study will provide the first high quality analysis of safety of CBD-enriched Cannabis herbal extract in pediatric patients in relation to dosage and pharmacokinetics of the active cannabinoids.TRIAL REGISTRATION: http://clinicaltrials.gov [Internet]. Bethesda (MD): National Library of Medicine (US). 2016 Dec 16. Identifier NCT03024827, Cannabidiol in Children with Refractory Epileptic Encephalopathy: CARE-E; 2017 Jan 19 [cited 2017 Oct]; Available from: http://clinicaltrials.gov/ct2/show/NCT03024827.

Database: PubMed

34. Composition and Use of Cannabis Extracts for Childhood Epilepsy in the Australian Community.

Author(s): Suraev A; Lintzeris N; Stuart J; Kevin RC; Blackburn R; Richards E; Arnold JC; Ireland C; Todd L; Allsop DJ; McGregor IS

Source: Scientific reports; Jul 2018; vol. 8 (no. 1); p. 10154

Publication Date: Jul 2018

Publication Type(s): Journal Article

PubMedID: 29977078

Available  at Scientific reports –  from ProQuest (Hospital Premium Collection) – NHS Version

Available  at Scientific reports –  from Europe PubMed Central – Open Access

Available  at Scientific reports –  from Nature Publishing Group – Open Access

Abstract:Recent surveys suggest that many parents are using illicit cannabis extracts in the hope of managing seizures in their children with epilepsy. In the current Australian study we conducted semi-structured interviews with families of children with diverse forms of epilepsy to explore their attitudes towards and experiences with using cannabis extracts. This included current or previous users of cannabis extracts to treat their child’s seizures (n = 41 families), and families who had never used (n = 24 families). For those using cannabis, extracts were analysed for cannabinoid content, with specific comparison of samples rated by families as “effective” versus those rated “ineffective”. Results showed that children given cannabis extracts tended to have more severe epilepsy historically and had trialled more anticonvulsants than those who had never received cannabis extracts. There was high variability in the cannabinoid content and profile of cannabis extracts rated as “effective”, with no clear differences between extracts perceived as “effective” and “ineffective”. Contrary to family’s expectations, most samples contained low concentrations of cannabidiol, while Δ9-tetrahydrocannabinol was present in nearly every sample. These findings highlight profound variation in the illicit cannabis extracts being currently used in Australia and warrant further investigations into the therapeutic value of cannabinoids in epilepsy.

Database: PubMed

35. The adult motor phenotype of Dravet syndrome is associated with mutation of the STXBP1 gene and responds well to cannabidiol treatment.

Author(s): Álvarez Bravo G; Yusta Izquierdo A

Source: Seizure; Aug 2018; vol. 60 ; p. 68-70

Publication Date: Aug 2018

Publication Type(s): Case Reports; Journal Article

PubMedID: 29929108

Available  at Seizure –  from ClinicalKey

Abstract:Dravet syndrome is a terrible disease generally caused by mutations of the SCN1A gene. Recently others genes such as STXBP1 have been involved in the pathogenesis of the disease. The STXBP1 mutation in patients with Dravet Syndrome may additionally causes several parkinsonian features usually attributed to carriers of the SCN1A mutation. Management continues to be difficult that is why Cannabidiol emerged as valid option for treatment of this condition.

Database: PubMed

36. Addition of Cannabidiol to Current Antiepileptic Therapy Reduces Drop Seizures in Children and Adults With Treatment-Resistant Lennox-Gastaut Syndrome.

Author(s): Ostrovsky DA; Ehrlich A

Source: Explore (New York, N.Y.); 2018; vol. 14 (no. 4); p. 311-313

Publication Date: 2018

Publication Type(s): Journal Article; Comment

PubMedID: 29887290

Database: PubMed

37. Investigational cannabinoids in seizure disorders, what have we learned thus far?

Author(s): Ružić Zečević D; Folić M; Tantoush Z; Radovanović M; Babić G; Janković SM

Source: Expert opinion on investigational drugs; Jun 2018; vol. 27 (no. 6); p. 535-541

Publication Date: Jun 2018

Publication Type(s): Journal Article; Review

PubMedID: 29842819

Abstract:INTRODUCTION: The anticonvulsant activity of cannabinoids attracted much attention in the last decade. Cannabinoids that are currently investigated with the intention of making them drugs for the treatment of epilepsy are cannabidiol, cannabidivarin, Δ9-tetrahydrocannabivarin, and Δ9-tetrahydrocannabinolic acid. Areas covered:In this review, the authors look at the results of preclinical and clinical studies with investigational cannabinoids. Relevant literature was searched for in MEDLINE, SCOPUS, EBSCO, GOOGLE SCHOLAR, and SCINDEX databases. Expert opinion: Preclinical studies confirmed anticonvulsant activity of cannabidiol and cannabidivarin in a variety of epilepsy models. While the results of clinical trials with cannabidivarin are still awaited, cannabidiol showed clear therapeutic benefit and good safety in patients with therapy-resistant seizures associated with Dravet syndrome and in patients with Lennox-Gastaut syndrome who have drop seizures. However, the full therapeutic potential of cannabinoids in treatment-resistant epilepsy needs to be investigated in the near future.

Database: PubMed

38. Review of the neurological benefits of phytocannabinoids.

Author(s): Maroon J; Bost J

Source: Surgical neurology international; 2018; vol. 9 ; p. 91

Publication Date: 2018

Publication Type(s): Journal Article; Review

PubMedID: 29770251

Available  at Surgical neurology international –  from ProQuest (Hospital Premium Collection) – NHS Version

Available  at Surgical neurology international –  from Europe PubMed Central – Open Access

Available  at Surgical neurology international –  from Unpaywall

Abstract:Background: Numerous physical, psychological, and emotional benefits have been attributed to marijuana since its first reported use in 2,600 BC in a Chinese pharmacopoeia. The phytocannabinoids, cannabidiol (CBD), and delta-9-tetrahydrocannabinol (Δ9-THC) are the most studied extracts from cannabis sativa subspecies hemp and marijuana. CBD and Δ9-THC interact uniquely with the endocannabinoid system (ECS). Through direct and indirect actions, intrinsic endocannabinoids and plant-based phytocannabinoids modulate and influence a variety of physiological systems influenced by the ECS.Methods: In 1980, Cunha et al. reported anticonvulsant benefits in 7/8 subjects with medically uncontrolled epilepsy using marijuana extracts in a phase I clinical trial. Since then neurological applications have been the major focus of renewed research using medical marijuana and phytocannabinoid extracts.Results: Recent neurological uses include adjunctive treatment for malignant brain tumors, Parkinson’s disease, Alzheimer’s disease, multiple sclerosis, neuropathic pain, and the childhood seizure disorders Lennox-Gastaut and Dravet syndromes. In addition, psychiatric and mood disorders, such as schizophrenia, anxiety, depression, addiction, postconcussion syndrome, and posttraumatic stress disorders are being studied using phytocannabinoids.Conclusions: In this review we will provide animal and human research data on the current clinical neurological uses for CBD individually and in combination with Δ9-THC. We will emphasize the neuroprotective, antiinflammatory, and immunomodulatory benefits of phytocannabinoids and their applications in various clinical syndromes.

Database: PubMed

39. Effect of Cannabidiol on Drop Seizures in the Lennox-Gastaut Syndrome.

Author(s): Devinsky O; Patel AD; Cross JH; Villanueva V; Wirrell EC; Privitera M; Greenwood SM; Roberts C; Checketts D; VanLandingham KE; Zuberi SM; GWPCARE3 Study Group

Source: The New England journal of medicine; May 2018; vol. 378 (no. 20); p. 1888-1897

Publication Date: May 2018

Publication Type(s): Clinical Trial, Phase III; Comparative Study; Journal Article; Multicenter Study; Randomized Controlled Trial; Research Support, Non-U.S. Gov’t

PubMedID: 29768152

Available  at The New England journal of medicine –  from Massachusetts Medical Society

Available  at The New England journal of medicine –  from ProQuest (Hospital Premium Collection) – NHS Version

Available  at The New England journal of medicine –  from University Hospitals of Derby and Burton NHS Foundation Trust Local Print Collection Print holdings: Latest five years: UHDB – Derby site<br><br>Print holdings: 2000 – 2018: UHDB – Burton site

Abstract:BACKGROUND: Cannabidiol has been used for treatment-resistant seizures in patients with severe early-onset epilepsy. We investigated the efficacy and safety of cannabidiol added to a regimen of conventional antiepileptic medication to treat drop seizures in patients with the Lennox-Gastaut syndrome, a severe developmental epileptic encephalopathy.METHODS: In this double-blind, placebo-controlled trial conducted at 30 clinical centers, we randomly assigned patients with the Lennox-Gastaut syndrome (age range, 2 to 55 years) who had had two or more drop seizures per week during a 28-day baseline period to receive cannabidiol oral solution at a dose of either 20 mg per kilogram of body weight (20-mg cannabidiol group) or 10 mg per kilogram (10-mg cannabidiol group) or matching placebo, administered in two equally divided doses daily for 14 weeks. The primary outcome was the percentage change from baseline in the frequency of drop seizures (average per 28 days) during the treatment period.RESULTS: A total of 225 patients were enrolled; 76 patients were assigned to the 20-mg cannabidiol group, 73 to the 10-mg cannabidiol group, and 76 to the placebo group. During the 28-day baseline period, the median number of drop seizures was 85 in all trial groups combined. The median percent reduction from baseline in drop-seizure frequency during the treatment period was 41.9% in the 20-mg cannabidiol group, 37.2% in the 10-mg cannabidiol group, and 17.2% in the placebo group (P=0.005 for the 20-mg cannabidiol group vs. placebo group, and P=0.002 for the 10-mg cannabidiol group vs. placebo group). The most common adverse events among the patients in the cannabidiol groups were somnolence, decreased appetite, and diarrhea; these events occurred more frequently in the higher-dose group. Six patients in the 20-mg cannabidiol group and 1 patient in the 10-mg cannabidiol group discontinued the trial medication because of adverse events and were withdrawn from the trial. Fourteen patients who received cannabidiol (9%) had elevated liver aminotransferase concentrations.CONCLUSIONS: Among children and adults with the Lennox-Gastaut syndrome, the addition of cannabidiol at a dose of 10 mg or 20 mg per kilogram per day to a conventional antiepileptic regimen resulted in greater reductions in the frequency of drop seizures than placebo. Adverse events with cannabidiol included elevated liver aminotransferase concentrations. (Funded by GW Pharmaceuticals; GWPCARE3 ClinicalTrials.gov number, NCT02224560 .).

Database: PubMed

40. Efficacy of CBD-enriched medical cannabis for treatment of refractory epilepsy in children and adolescents – An observational, longitudinal study.

Author(s): Hausman-Kedem M; Menascu S; Kramer U

Source: Brain & development; Aug 2018; vol. 40 (no. 7); p. 544-551

Publication Date: Aug 2018

Publication Type(s): Journal Article; Observational Study

PubMedID: 29674131

Available  at Brain & development –  from ClinicalKey

Abstract:The objective of this observational study was to evaluate the efficacy of medical cannabis for the treatment of refractory epilepsy. Fifty-seven patients (age 1-20 years) with epilepsy of various etiologies were treated with Cannabis oil extract (CBD/THC ratio of 20:1) for at least 3 months (Median follow up time-18 months). Forty-Six Patients were included in the efficacy analysis. Average CBD dose was11.4 mg/kg/d. Twenty-six patients (56%) had ≤50% reduction in mean monthly seizure frequency. There was no statistically significant difference in response rate among various epilepsy etiologies, and cannabis strain used. Younger age at treatment onset (11 mg/kg/d) were associated with better response to treatment. Adverse reactions were reported in 46% of patients and were the main reason for treatment cessation. Our results suggest that adding CBD-enriched cannabis extract to the treatment regimen of patients with refractory epilepsy may result in a significant reduction in seizure frequency according to parental reports. Randomized controlled trials are necessary to assess its true efficacy.

Database: PubMed

41. Treatment Strategies for Dravet Syndrome.

Author(s): Knupp KG; Wirrell EC

Source: CNS drugs; Apr 2018; vol. 32 (no. 4); p. 335-350

Publication Date: Apr 2018

Publication Type(s): Journal Article; Review

PubMedID: 29594870

Abstract:Dravet syndrome (DS) is a medically refractory epilepsy that onsets in the first year of life with prolonged seizures, often triggered by fever. Over time, patients develop other seizure types (myoclonic, atypical absences, drops), intellectual disability, crouch gait and other co-morbidities (sleep problems, autonomic dysfunction). Complete seizure control is generally not achievable with current therapies, and the goals of treatment are to balance reduction of seizure burden with adverse effects of therapies. Treatment of co-morbidities must also be addressed, as they have a significant impact on the quality of life of patients with DS. Seizures are typically worsened with sodium-channel agents. Accepted first-line agents include clobazam and valproic acid, although these rarely provide adequate seizure control. Benefit has also been noted with topiramate, levetiracetam, the ketogenic diet and vagal nerve stimulation. Several agents presently in development, specifically fenfluramine and cannabidiol, have shown efficacy in clinical trials. Status epilepticus is a recurring problem for patients with DS, particularly in their early childhood years. All patients should be prescribed a home rescue therapy (usually a benzodiazepine) but should also have a written seizure action plan that outlines when rescue should be given and further steps to take in the local hospital if the seizure persists despite home rescue therapy.

Database: PubMed

42. Cannabidiol exerts antiepileptic effects by restoring hippocampal interneuron functions in a temporal lobe epilepsy model.

Author(s): Khan AA; Shekh-Ahmad T; Khalil A; Walker MC; Ali AB

Source: British journal of pharmacology; Jun 2018; vol. 175 (no. 11); p. 2097-2115

Publication Date: Jun 2018

Publication Type(s): Journal Article

PubMedID: 29574880

Available  at British journal of pharmacology –  from Wiley

Abstract:BACKGROUND AND PURPOSE: A non-psychoactive phytocannabinoid, cannabidiol (CBD), shows promising results as an effective potential antiepileptic drug in some forms of refractory epilepsy. To elucidate the mechanisms by which CBD exerts its anti-seizure effects, we investigated its effects at synaptic connections and on the intrinsic membrane properties of hippocampal CA1 pyramidal cells and two major inhibitory interneurons: fast spiking, parvalbumin (PV)-expressing and adapting, cholecystokinin (CCK)-expressing interneurons. We also investigated whether in vivo treatment with CBD altered the fate of CCK and PV interneurons using immunohistochemistry.EXPERIMENTAL APPROACH: Electrophysiological intracellular whole-cell recordings combined with neuroanatomy were performed in acute brain slices of rat temporal lobe epilepsy in in vivo (induced by kainic acid) and in vitro (induced by Mg2+ -free solution) epileptic seizure models. For immunohistochemistry experiments, CBD was administered in vivo (100 mg·kg-1 ) at zero time and 90 min post status epilepticus, induced with kainic acid.KEY RESULTS: Bath application of CBD (10 μM) dampened excitability at unitary synapses between pyramidal cells but enhanced inhibitory synaptic potentials elicited by fast spiking and adapting interneurons at postsynaptic pyramidal cells. Furthermore, CBD restored impaired membrane excitability of PV, CCK and pyramidal cells in a cell type-specific manner. These neuroprotective effects of CBD were corroborated by immunohistochemistry experiments that revealed a significant reduction in atrophy and death of PV- and CCK-expressing interneurons after CBD treatment.CONCLUSIONS AND IMPLICATIONS: Our data suggest that CBD restores excitability and morphological impairments in epileptic models to pre-epilepsy control levels through multiple mechanisms to reinstate normal network function.

Database: PubMed

43. Randomized, dose-ranging safety trial of cannabidiol in Dravet syndrome.

Author(s): Devinsky O; Patel AD; Thiele EA; Wong MH; Appleton R; Harden CL; Greenwood S; Morrison G; Sommerville K; GWPCARE1 Part A Study Group

Source: Neurology; Apr 2018; vol. 90 (no. 14); p. e1204-e1211

Publication Date: Apr 2018

Publication Type(s): Journal Article

PubMedID: 29540584

Available  at Neurology –  from American Academy of Neurology Please note that full text is not available for all the issues of this title.

Available  at Neurology –  from Unpaywall

Abstract:OBJECTIVE: To evaluate the safety and preliminary pharmacokinetics of a pharmaceutical formulation of purified cannabidiol (CBD) in children with Dravet syndrome.METHODS: Patients aged 4-10 years were randomized 4:1 to CBD (5, 10, or 20 mg/kg/d) or placebo taken twice daily. The double-blind trial comprised 4-week baseline, 3-week treatment (including titration), 10-day taper, and 4-week follow-up periods. Completers could continue in an open-label extension. Multiple pharmacokinetic blood samples were taken on the first day of dosing and at end of treatment for measurement of CBD, its metabolites 6-OH-CBD, 7-OH-CBD, and 7-COOH-CBD, and antiepileptic drugs (AEDs; clobazam and metabolite N-desmethylclobazam [N-CLB], valproate, levetiracetam, topiramate, and stiripentol). Safety assessments were clinical laboratory tests, physical examinations, vital signs, ECGs, adverse events (AEs), seizure frequency, and suicidality.RESULTS: Thirty-four patients were randomized (10, 8, and 9 to the 5, 10, and 20 mg/kg/d CBD groups, and 7 to placebo); 32 (94%) completed treatment. Exposure to CBD and its metabolites was dose-proportional (AUC0-t). CBD did not affect concomitant AED levels, apart from an increase in N-CLB (except in patients taking stiripentol). The most common AEs on CBD were pyrexia, somnolence, decreased appetite, sedation, vomiting, ataxia, and abnormal behavior. Six patients taking CBD and valproate developed elevated transaminases; none met criteria for drug-induced liver injury and all recovered. No other clinically relevant safety signals were observed.CONCLUSIONS: Exposure to CBD and its metabolites increased proportionally with dose. An interaction with N-CLB was observed, likely related to CBD inhibition of cytochrome P450 subtype 2C19. CBD resulted in more AEs than placebo but was generally well-tolerated.CLASSIFICATION OF EVIDENCE: This study provides Class I evidence that for children with Dravet syndrome, CBD resulted in more AEs than placebo but was generally well-tolerated.

Database: PubMed

44. Cannabidiol for treatment of refractory childhood epilepsies: Experience from a single tertiary epilepsy center in Slovenia.

Author(s): Neubauer D; Perković Benedik M; Osredkar D

Source: Epilepsy & behavior : E&B; 2018; vol. 81 ; p. 79-85

Publication Date: 2018

Publication Type(s): Journal Article

PubMedID: 29526578

Available  at Epilepsy & behavior : E&B –  from ClinicalKey

Abstract:PURPOSE: Refractory epilepsies in children present a major burden for patients and their families. Cannabidiol (CBD) has been suggested as a potential treatment for refractory epilepsies. The aim of this study was to evaluate the effectiveness of add-on therapy with CBD for the treatment of refractory childhood epilepsies.METHOD: Patients with childhood-onset refractory epilepsy, treated at the tertiary epilepsy center of the University Children’s Hospital Ljubljana, Slovenia, were included in the study. Add-on therapy with CBD was initiated once the child’s epilepsy was categorized as pharmacoresistant to other antiepileptic drugs/therapies. The dosage of CBD was gradually increased to at least 8mg/kg/day. The effect of CBD treatment was evaluated by the reduction in seizure burden and presence of side effects (positive and negative). Serial electroencephalography was performed in some children.RESULTS: Sixty-six patients were included in the analysis. Thirty-two (48.5%) patients had a more than 50% improvement regarding seizure burden, 14 of whom (21.2%) became seizure-free. None of the patients reported worsening of seizure frequency, but CBD had no effect in 15 (22.7%) patients. Some patients reported less vigorous seizures, shorter duration of seizures, shorter time to recovery, and other positive side effects of CBD treatment. Adverse effects were reported in 5/66 children.CONCLUSIONS: In our cohort of patients, CBD was found to have potential benefits as add-on therapy for refractory childhood epilepsies, mainly by reducing seizure burden.

Database: PubMed

45. Evidence for cannabis and cannabinoids for epilepsy: a systematic review of controlled and observational evidence.

Author(s): Stockings E; Zagic D; Campbell G; Weier M; Hall WD; Nielsen S; Herkes GK; Farrell M; Degenhardt L

Source: Journal of neurology, neurosurgery, and psychiatry; Jul 2018; vol. 89 (no. 7); p. 741-753

Publication Date: Jul 2018

Publication Type(s): Journal Article; Review

PubMedID: 29511052

Available  at Journal of neurology, neurosurgery, and psychiatry –  from BMJ Journals – NHS

Available  at Journal of neurology, neurosurgery, and psychiatry –  from ProQuest (Hospital Premium Collection) – NHS Version

Available  at Journal of neurology, neurosurgery, and psychiatry –  from Unpaywall

Abstract:Review evidence for cannabinoids as adjunctive treatments for treatment-resistant epilepsy. Systematic search of Medline, Embase and PsycINFO was conducted in October 2017. Outcomes were: 50%+ seizure reduction, complete seizure freedom; improved quality of life (QoL). Tolerability/safety were assessed by study withdrawals, adverse events (AEs) and serious adverse events (SAEs). Analyses were conducted in Stata V.15.0. 36 studies were identified: 6 randomised controlled trials (RCTs), 30 observational studies. Mean age of participants was 16.1 years (range 0.5-55 years). Cannabidiol (CBD) 20 mg/kg/day was more effective than placebo at reducing seizure frequency by 50%+(relative risk (RR) 1.74, 95% CI 1.24 to 2.43, 2 RCTs, 291 patients, low Grades of Recommendation, Assessment, Development and Evaluation (GRADE) rating). The number needed to treat for one person using CBD to experience 50%+ seizure reduction was 8 (95% CI 6 to 17). CBD was more effective than placebo at achieving complete seizure freedom (RR 6.17, 95% CI 1.50 to 25.32, 3 RCTs, 306 patients, low GRADE rating), and improving QoL (RR 1.73, 95% CI 1.33 to 2.26), however increased risk of AEs (RR 1.24, 95% CI 1.13 to 1.36) and SAEs (RR 2.55, 95% CI 1.48 to 4.38). Pooled across 17 observational studies, 48.5% (95% CI 39.0% to 58.1%) of patients reported 50%+ reductions in seizures; in 14 observational studies 8.5% (95% CI 3.8% to 14.5%) were seizure-free. Twelve observational studies reported improved QoL (55.8%, 95% CI 40.5 to 70.6); 50.6% (95% CI 31.7 to 69.4) AEs and 2.2% (95% CI 0 to 7.9) SAEs. Pharmaceutical-grade CBD as adjuvant treatment in paediatric-onset drug-resistant epilepsy may reduce seizure frequency. Existing RCT evidence is mostly in paediatric samples with rare and severe epilepsy syndromes; RCTs examining other syndromes and cannabinoids are needed.PROSPERO REGISTRATION NUMBER: CRD42017055412.

Database: PubMed

46. Cannabidiol Regulates Long Term Potentiation Following Status Epilepticus: Mediation by Calcium Stores and Serotonin.

Author(s): Maggio N; Shavit Stein E; Segal M

Source: Frontiers in molecular neuroscience; 2018; vol. 11 ; p. 32

Publication Date: 2018

Publication Type(s): Journal Article

PubMedID: 29467619

Available  at Frontiers in molecular neuroscience –  from Europe PubMed Central – Open Access

Available  at Frontiers in molecular neuroscience –  from Unpaywall

Abstract:Epilepsy is a devastating disease, with cognitive and emotional consequences that are not curable. In recent years, it became apparent that cannabinoids help patients to cope with epilepsy. We have studied the effects of cannabidiol (CBD) on the ability to produce long term potentiation (LTP) in stratum radiatum of CA1 region of the mouse hippocampus. Exposure to seizure-producing pilocarpine reduced the ability to generate LTP in the slice. Pre-exposure to CBD prevented this effect of pilocarpine. Furthermore, CBD caused a marked increase in ability to generate LTP, an effect that was blocked by calcium store antagonists as well as by a reduction in serotonin tone. Serotonin, possibly acting at a 5HT1A receptor, or fenfluramine (FFA), which causes release of serotonin from its native terminals, mimicked the effect of CBD. It is proposed that CBD enhances non-NMDA LTP in the slice by facilitating release of serotonin from terminals, consequently ameliorating the detrimental effects of pilocarpine.

Database: PubMed

47. Cannabis for paediatric epilepsy: challenges and conundrums.

Author(s): Chen KA; Farrar MA; Cardamone M; Lawson JA

Source: The Medical journal of Australia; Feb 2018; vol. 208 (no. 3); p. 132-136

Publication Date: Feb 2018

Publication Type(s): Journal Article

PubMedID: 29438649

Available  at The Medical journal of Australia –  from University Hospitals of Derby and Burton NHS Foundation Trust Local Print Collection Print Holdings: Latest Five years.[location] : RDH,Derby Hospitals NHS Foundation Trust., [location] : Print Holdings Latest Five years.  RDH,Derby Hospitals NHS Foundation Trust.

Abstract:Research is expanding for the use of cannabidiol as an anticonvulsant drug. The mechanism of cannabidiol in paediatric epilepsy is unclear but is thought to play a role in modulation of synaptic transmission. Evidence for its efficacy in treating epilepsy is limited but growing, with a single pharmaceutical company-funded randomised double-blind controlled trial in children with Dravet syndrome. Progress towards the use of medicinal cannabinoids incorporates a complex interplay of social influences and political and legal reform. Access to unregistered but available cannabidiol in Australia outside of clinical trials and compassionate access schemes is state dependent and will require Therapeutic Goods Administration approval, although the cost may be prohibitive. Further clinical trials are needed to clearly define efficacy and safety, particularly long term.

Database: PubMed

48. Cannabidiol in patients with seizures associated with Lennox-Gastaut syndrome (GWPCARE4): a randomised, double-blind, placebo-controlled phase 3 trial.

Author(s): Thiele EA; Marsh ED; French JA; Mazurkiewicz-Beldzinska M; Benbadis SR; Joshi C; Lyons PD; Taylor A; Roberts C; Sommerville K; GWPCARE4 Study Group

Source: Lancet (London, England); ; vol. 391 (no. 10125); p. 1085-1096

Publication Type(s): Clinical Trial, Phase III; Journal Article; Randomized Controlled Trial; Research Support, Non-U.S. Gov’t

PubMedID: 29395273

Available  at Lancet (London, England) –  from ClinicalKey

Available  at Lancet (London, England) –  from ProQuest (Hospital Premium Collection) – NHS Version

Abstract:BACKGROUND: Patients with Lennox-Gastaut syndrome, a rare, severe form of epileptic encephalopathy, are frequently treatment resistant to available medications. No controlled studies have investigated the use of cannabidiol for patients with seizures associated with Lennox-Gastaut syndrome. We therefore assessed the efficacy and safety of cannabidiol as an add-on anticonvulsant therapy in this population of patients.METHODS: In this randomised, double-blind, placebo-controlled trial done at 24 clinical sites in the USA, the Netherlands, and Poland, we investigated the efficacy of cannabidiol as add-on therapy for drop seizures in patients with treatment-resistant Lennox-Gastaut syndrome. Eligible patients (aged 2-55 years) had Lennox-Gastaut syndrome, including a history of slow (<3 Hz) spike-and-wave patterns on electroencephalogram, evidence of more than one type of generalised seizure for at least 6 months, at least two drop seizures per week during the 4-week baseline period, and had not responded to treatment with at least two antiepileptic drugs. Patients were randomly assigned (1:1) using an interactive voice response system, stratified by age group, to receive 20 mg/kg oral cannabidiol daily or matched placebo for 14 weeks. All patients, caregivers, investigators, and individuals assessing data were masked to group assignment. The primary endpoint was percentage change from baseline in monthly frequency of drop seizures during the treatment period, analysed in all patients who received at least one dose of study drug and had post-baseline efficacy data. All randomly assigned patients were included in the safety analyses. This study is registered with ClinicalTrials.gov, number NCT02224690.FINDINGS: Between April 28, 2015, and Oct 15, 2015, we randomly assigned 171 patients to receive cannabidiol (n=86) or placebo (n=85). 14 patients in the cannabidiol group and one in the placebo group discontinued study treatment; all randomly assigned patients received at least one dose of study treatment and had post-baseline efficacy data. The median percentage reduction in monthly drop seizure frequency from baseline was 43·9% (IQR -69·6 to -1·9) in the cannibidiol group and 21·8% (IQR -45·7 to 1·7) in the placebo group. The estimated median difference between the treatment groups was -17·21 (95% CI -30·32 to -4·09; p=0·0135) during the 14-week treatment period. Adverse events occurred in 74 (86%) of 86 patients in the cannabidiol group and 59 (69%) of 85 patients in the placebo group; most were mild or moderate. The most common adverse events were diarrhoea, somnolence, pyrexia, decreased appetite, and vomiting. 12 (14%) patients in the cannabidiol group and one (1%) patient in the placebo group withdrew from the study because of adverse events. One patient (1%) died in the cannabidiol group, but this was considered unrelated to treatment.INTERPRETATION: Add-on cannabidiol is efficacious for the treatment of patients with drop seizures associated with Lennox-Gastaut syndrome and is generally well tolerated. The long-term efficacy and safety of cannabidiol is currently being assessed in the open-label extension of this trial.FUNDING: GW Pharmaceuticals.

Database: PubMed

49. Prospects of Cannabidiol for Easing Status Epilepticus-Induced Epileptogenesis and Related Comorbidities.

Author(s): Upadhya D; Castro OW; Upadhya R; Shetty AK

Source: Molecular neurobiology; Aug 2018; vol. 55 (no. 8); p. 6956-6964

Publication Date: Aug 2018

Publication Type(s): Journal Article; Review

PubMedID: 29372545

Abstract:The hippocampus is one of the most susceptible regions in the brain to be distraught with status epilepticus (SE) induced injury. SE can occur from numerous causes and is more frequent in children and the elderly population. Administration of a combination of antiepileptic drugs can abolish acute seizures in most instances of SE but cannot prevent the morbidity typically seen in survivors of SE such as cognitive and mood impairments and spontaneous recurrent seizures. This is primarily due to the inefficiency of antiepileptic drugs to modify the evolution of SE-induced initial precipitating injury into a series of epileptogenic changes followed by a state of chronic epilepsy. Chronic epilepsy is typified by spontaneous recurrent seizures, cognitive dysfunction, and depression, which are associated with persistent inflammation, significantly waned neurogenesis, and abnormal synaptic reorganization. Thus, alternative approaches that are efficient not only for curtailing SE-induced initial brain injury, neuroinflammation, aberrant neurogenesis, and abnormal synaptic reorganization but also for thwarting or restraining the progression of SE into a chronic epileptic state are needed. In this review, we confer the promise of cannabidiol, an active ingredient of Cannabis sativa, for preventing or easing SE-induced neurodegeneration, neuroinflammation, cognitive and mood impairments, and the spontaneous recurrent seizures.

Database: PubMed

50. Cannabinoids in the Treatment of Epilepsy: Hard Evidence at Last?

Author(s): Perucca E

Source: Journal of epilepsy research; Dec 2017; vol. 7 (no. 2); p. 61-76

Publication Date: Dec 2017

Publication Type(s): Journal Article; Review

PubMedID: 29344464

Available  at Journal of epilepsy research –  from Europe PubMed Central – Open Access

Available  at Journal of epilepsy research –  from Unpaywall

Abstract:The interest in cannabis-based products for the treatment of refractory epilepsy has skyrocketed in recent years. Marijuana and other cannabis products with high content in Δ(9) – tetrahydrocannabinol (THC), utilized primarily for recreational purposes, are generally unsuitable for this indication, primarily because THC is associated with many undesired effects. Compared with THC, cannabidiol (CBD) shows a better defined anticonvulsant profile in animal models and is largely devoid of adverse psychoactive effects and abuse liability. Over the years, this has led to an increasing use of CBD-enriched extracts in seizure disorders, particularly in children. Although improvement in seizure control and other benefits on sleep and behavior have been often reported, interpretation of the data is made difficult by the uncontrolled nature of these observations. Evidence concerning the potential anti-seizure efficacy of cannabinoids reached a turning point in the last 12 months, with the completion of three high-quality placebo-controlled adjunctive-therapy trials of a purified CBD product in patients with Dravet syndrome and Lennox-Gastaut syndrome. In these studies, CBD was found to be superior to placebo in reducing the frequency of convulsive (tonic-clonic, tonic, clonic, and atonic) seizures in patients with Dravet syndrome, and the frequency of drop seizures in patients with Lennox-Gastaut syndrome. For the first time, there is now class 1 evidence that adjunctive use of CBD improves seizure control in patients with specific epilepsy syndromes. Based on currently available information, however, it is unclear whether the improved seizure control described in these trials was related to a direct action of CBD, or was mediated by drug interactions with concomitant medications, particularly a marked increased in plasma levels of N-desmethylclobazam, the active metabolite of clobazam. Clarification of the relative contribution of CBD to improved seizure outcome requires re-assessment of trial data for the subgroup of patients not comedicated with clobazam, or the conduction of further studies controlling for the confounding effect of this interaction.

Database: PubMed

51. Do Cannabinoids Confer Neuroprotection Against Epilepsy? An Overview.

Author(s): Capasso A

Source: The open neurology journal; 2017; vol. 11 ; p. 61-73

Publication Date: 2017

Publication Type(s): Journal Article; Review

PubMedID: 29290836

Available  at The open neurology journal –  from Europe PubMed Central – Open Access

Available  at The open neurology journal –  from Unpaywall

Abstract:Objective: Cannabinoid-based medications provide not only relief for specific symptoms, but also arrest or delay of disease progression in patients with pain, multiple sclerosis, and other conditions. Although they also seem to hold potential as anticonvulsant agents, evidence of their efficacy in epilepsy is supported by several evidences.Method: The data reviewed herein lend support to the notion that the endocannabinoid signalling system plays a key modulation role in the activities subserved by the hippocampus, which is directly or indirectly affected in epilepsy patients.Conclusion: The notion is supported by a variety of anatomical, electrophysiological, biochemical and pharmacological findings. These data suggest the need for developing novel treatments using compounds that selectively target individual elements of the endocannabinoid signalling system.

Database: PubMed

52. Cannabinoids for epilepsy: What do we know and where do we go?

Author(s): Brodie MJ; Ben-Menachem E

Source: Epilepsia; 2018; vol. 59 (no. 2); p. 291-296

Publication Date: 2018

Publication Type(s): Journal Article; Review

PubMedID: 29214639

Available  at Epilepsia –  from Wiley

Available  at Epilepsia –  from IngentaConnect

Abstract:Over the past decade there has been an increasing interest in using cannabinoids to treat a range of epilepsy syndromes following reports of some remarkable responses in individual patients. The situation is complicated by the fact that these agents do not appear to work via their attachment to endogenous cannabinoid receptors. Their pharmacokinetics are complex, and bioavailability is variable, resulting in difficulty in developing a suitable formulation for oral delivery. Drug interactions also represent another complication in their everyday use. Nevertheless, recent randomized, placebo-controlled trials with cannabidiol support its efficacy in Dravet and Lennox-Gastaut syndromes. Further placebo-controlled studies are underway in adults with focal epilepsy using cannabidivarin. The many unanswered questions in the use of cannabinoids to treat epileptic seizures are briefly summarized in the conclusion.

Database: PubMed

53. Efficacy and safety of cannabis for treating children with refractory epilepsy.

Author(s): Neale M

Source: Nursing children and young people; Sep 2017; vol. 29 (no. 7); p. 32-37

Publication Date: Sep 2017

Publication Type(s): Journal Article; Review

PubMedID: 29115760

Abstract:The aim of this literature review was to examine the evidence base for the safety and efficacy of cannabis in treating children with refractory epilepsy. Clinical and medical databases were searched and four articles were included in the final analysis, which included retrospective reviews and open-label trials with a total sample size of 424. One clinical trial included administration of cannabidiol, the non-psychoactive compound of cannabis, while the other three articles stated that the compound administered to participants contained tetrahydrocannabidiol, the psychoactive constituent of cannabis. Cannabis may reduce seizures in some children and young people with refractory epilepsy, however, its success may be affected by aetiology of the epilepsy or concomitant anti-epileptic drug use, and a therapeutic dose has not been found. Positive side effects were also found including improved sleep, alertness and mood. More research is needed on this subject, including randomised controlled trials. Nurses who are aware of patients and families wishing to trial cannabis for refractory epilepsy should have full and frank discussions.

Database: PubMed

54. The use of cannabidiol for seizure management in patients with brain tumor-related epilepsy.

Author(s): Warren PP; Bebin EM; Nabors LB; Szaflarski JP

Source: Neurocase; 2017; vol. 23 (no. 5-6); p. 287-291

Publication Date: 2017

Publication Type(s): Journal Article

PubMedID: 29063814

Abstract:Epilepsy, commonly encountered by patients with brain tumors, is often refractory to standard therapies. Our aim was to examine the safety and efficacy of pharmaceutical grade cannabidiol (CBD; Epidiolex; Greenwich Biosciences) in those patients with epilepsy with concomitant tumors enrolled in The University of Alabama at Birmingham CBD Program (NCT02700412 and NCT02695537). Of the three patients with refractory seizures and a history of a primary brain tumor, two had improvement in seizure frequency and all three had improvement in seizure severity. These pilot results suggest that CBD should be further studied for the treatment of brain tumor-related epilepsy.

Database: PubMed

55. Medical Cannabinoids in Children and Adolescents: A Systematic Review.

Author(s): Wong SS; Wilens TE

Source: Pediatrics; Nov 2017; vol. 140 (no. 5)

Publication Date: Nov 2017

Publication Type(s): Case Reports; Journal Article; Review; Systematic Review

PubMedID: 29061872

Available  at Pediatrics –  from HighWire – Free Full Text Full text is available free online for 4 years following an initial 1-year embargo after publication.

Abstract:CONTEXT: Legalization of medical marijuana in many states has led to a widening gap between the accessibility and the evidence for cannabinoids as a medical treatment.OBJECTIVE: To systematically review published reports to identify the evidence base of cannabinoids as a medical treatment in children and adolescents.DATA SOURCES: Based on Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, a search of PubMed, Medline, and the Cumulative Index to Nursing and Allied Health Literature databases was conducted in May 2017.STUDY SELECTION: Searching identified 2743 citations, and 103 full texts were reviewed.DATA EXTRACTION: Searching identified 21 articles that met inclusion criteria, including 22 studies with a total sample of 795 participants. Five randomized controlled trials, 5 retrospective chart reviews, 5 case reports, 4 open-label trials, 2 parent surveys, and 1 case series were identified.RESULTS: Evidence for benefit was strongest for chemotherapy-induced nausea and vomiting, with increasing evidence of benefit for epilepsy. At this time, there is insufficient evidence to support use for spasticity, neuropathic pain, posttraumatic stress disorder, and Tourette syndrome.LIMITATIONS: The methodological quality of studies varied, with the majority of studies lacking control groups, limited by small sample size, and not designed to test for the statistical significance of outcome measures. Studies were heterogeneous in the cannabinoid composition and dosage and lacked long-term follow-up to identify potential adverse effects.CONCLUSIONS: Additional research is needed to evaluate the potential role of medical cannabinoids in children and adolescents, especially given increasing accessibility from state legalization and potential psychiatric and neurocognitive adverse effects identified from studies of recreational cannabis use.

Database: PubMed

56. A resurging boom in new drugs for epilepsy and brain disorders.

Author(s): Younus I; Reddy DS

Source: Expert review of clinical pharmacology; Jan 2018; vol. 11 (no. 1); p. 27-45

Publication Date: Jan 2018

Publication Type(s): Journal Article; Review

PubMedID: 28956955

Abstract:INTRODUCTION: Epilepsy is one of the most common neurological diseases affecting approximately 50 million people worldwide. Despite many advances in epilepsy research, nearly a third of patients with epilepsy have refractory or pharmacoresistant epilepsy. Despite the approval of a dozen antiepileptic drugs (AEDs) over the past decade, there are no agents that halt the development of epilepsy. Thus, newer and better AEDs that can prevent refractory seizures and modify the disease are needed for curing epilepsy. Areas covered: In this article, we highlight the recent advances and emerging trends in new and innovative drugs for epilepsy and seizure disorders. We review in detail top new drugs that are currently in clinical trials or agents that are under development and have novel mechanisms of action. Expert commentary: Among the new agents under clinical investigation, the majority were originally developed for treating other neurological diseases (everolimus, fenfluramine, nalutozan, bumetanide, and valnoctamide); several have mechanisms of action similar to those of conventional AEDs (AP, ganaxolone, and YKP3089); and some new agents represent novel mechanisms of actions (huperzine-A, cannabidiol, tonabersat, and VX-765).

Database: PubMed

57. [Cannabis use in Epilepsy. Current situation in Argentina and abroad].

Author(s): Kochen S

Source: Vertex (Buenos Aires, Argentina); Nov 2016 (no. 130); p. 457-462

Publication Date: Nov 2016

Publication Type(s): Journal Article

PubMedID: 28898306

Abstract:Although at present we have over 20 different types of drugs for epilepsy, 30 to 40% of patients continue to have seizures. Preliminary data from human studies suggest that cannabis, cannabidiol in particular, is effective in the treatment of some patients with epilepsy. However, the available data are limited and do not allow defnitive conclusions. Only randomized clinical trials with controlled double-blind, placebo-controlled utilizing secure preparations and one or more cannabinoids, will provide comprehensive information on the effcacy and safety of use. In order to perform these trials it is necessary to have legislation authorizing the use of cannabis on epilepsy.

Database: PubMed

58. The potential role of cannabinoids in epilepsy treatment.

Author(s): De Caro C; Leo A; Citraro R; De Sarro C; Russo R; Calignano A; Russo E

Source: Expert review of neurotherapeutics; Nov 2017; vol. 17 (no. 11); p. 1069-1079

Publication Date: Nov 2017

Publication Type(s): Journal Article; Review

PubMedID: 28845714

Abstract:INTRODUCTION: Epilepsy is one of the world’s oldest recognized and prevalent neurological diseases. It has a great negative impact on patients’ quality of life (QOL) as a consequence of treatment resistant seizures in about 30% of patients together with drugs’ side effects and comorbidities. Therefore, new drugs are needed and cannabinoids, above all cannabidiol, have recently gathered attention. Areas covered: This review summarizes the scientific data from human and animal studies on the major cannabinoids which have been of interest in the treatment of epilepsy, including drugs acting on the endocannabinoid system. Expert commentary: Despite the fact that cannabis has been used for many purposes over 4 millennia, the development of drugs based on cannabinoids has been very slow. Only recently, research has focused on their potential effects and CBD is the first treatment of this group with clinical evidence of efficacy in children with Dravet syndrome; moreover, other studies are currently ongoing to confirm its effectiveness in patients with epilepsy. On the other hand, it will be of interest to understand whether drugs acting on the endocannabinoid system will be able to reach the market and prove their known preclinical efficacy also in patients with epilepsy.

Database: PubMed

59. Interactions between cannabidiol and commonly used antiepileptic drugs.

Author(s): Gaston TE; Bebin EM; Cutter GR; Liu Y; Szaflarski JP; UAB CBD Program

Source: Epilepsia; 2017; vol. 58 (no. 9); p. 1586-1592

Publication Date: 2017

Publication Type(s): Journal Article

PubMedID: 28782097

Available  at Epilepsia –  from IngentaConnect – Open Access

Available  at Epilepsia –  from Wiley

Available  at Epilepsia –  from IngentaConnect

Abstract:OBJECTIVE: To identify potential pharmacokinetic interactions between the pharmaceutical formulation of cannabidiol (CBD; Epidiolex) and the commonly used antiepileptic drugs (AEDs) through an open-label safety study. Serum levels were monitored to identify interactions between CBD and AEDs.METHODS: In 39 adults and 42 children, CBD dose was started at 5 mg/kg/day and increased every 2 weeks by 5 mg/kg/day up to a maximum of 50 mg/kg/day. Serum AED levels were obtained at baseline prior to CBD initiation and at most study visits. AED doses were adjusted if it was determined that a clinical symptom or laboratory result was related to a potential interaction. The Mixed Procedure was used to determine if there was a significant change in the serum level of each of the 19 AEDs with increasing CBD dose. AEDs with interactions seen in initial analysis were plotted for mean change in serum level over time. Subanalyses were performed to determine if the frequency of sedation in participants was related to the mean serum N-desmethylclobazam level, and if aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were different in participants taking concomitant valproate.RESULTS: Increases in topiramate, rufinamide, and N-desmethylclobazam and decrease in clobazam (all p < 0.01) serum levels were seen with increasing CBD dose. Increases in serum levels of zonisamide (p = 0.02) and eslicarbazepine (p = 0.04) with increasing CBD dose were seen in adults. Except for clobazam and desmethylclobazam, all noted mean level changes were within the accepted therapeutic range. Sedation was more frequent with higher N-desmethylclobazam levels in adults (p = 0.02), and AST/ALT levels were significantly higher in participants taking concomitant valproate (p < 0.01).SIGNIFICANCE: Significantly changed serum levels of clobazam, rufinamide, topiramate, zonisamide, and eslicarbazepine were seen. Abnormal liver function test results were noted in participants taking concomitant valproate. This study emphasizes the importance of monitoring serum AED levels and LFTs during treatment with CBD.

Database: PubMed

60. Could Cannabidiol be a Treatment Option for Intractable Childhood and Adolescent Epilepsy?

Author(s): Koo CM; Kang HC

Source: Journal of epilepsy research; Jun 2017; vol. 7 (no. 1); p. 16-20

Publication Date: Jun 2017

Publication Type(s): Journal Article; Review

PubMedID: 28775950

Available  at Journal of epilepsy research –  from Europe PubMed Central – Open Access

Available  at Journal of epilepsy research –  from Unpaywall

Abstract:Epilepsy is an important disease that affects brain function, particularly in those under 3 years old. Uncontrolled seizures can affect cognitive function and quality of life. For these reasons, many trials have been conducted to investigate treatments for pediatric epilepsy. Currently, many antiepileptic drugs are available for the treatment of epilepsy, but cases of intractable epilepsy continue to exist. In the past, cannabis has been tested as a potential treatment of intractable epilepsy. Since 2013, 10 epilepsy centers in America have conducted research regarding the efficacy of cannabis to treat epilepsy. Cannabis has many components, including cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC). THC has psychoactive properties exerted through its binding of the cannabinoid receptor (CBR) whereas CBD is a CBR antagonist. The inhibition of epilepsy by CBD may therefore be caused by various mechanisms, although the detailed mechanisms of CBD actions have not yet been well defined. In most studies, trial doses of CBD were 2-5 mg/kg/day. Several such studies have shown that CBD does have efficacy for treatment of epilepsy. Reported adverse effects of CBD were mostly mild, including drowsiness, diarrhea, and decreased appetite. Severe adverse reactions requiring treatment, such as status epilepticus, have also been reported but it is not clear that this is related to CBD. Furthermore, many previous studies have been limited by an open-label or survey design. In future, double-blind, controlled trials are required and the use of CBD to treat other neurological problems should also be investigated.

Database: PubMed

61. [Cannabidiol: its use in refractory epilepsies].

Author(s): Pesantez-Rios G; Armijos-Acurio L; Jimbo-Sotomayor R; Pascual-Pascual SI; Pesantez-Cuesta G

Source: Revista de neurologia; Aug 2017; vol. 65 (no. 4); p. 157-160

Publication Date: Aug 2017

Publication Type(s): Journal Article; Observational Study

PubMedID: 28726233

Abstract:INTRODUCTION: Some epileptic syndromes are characterised by seizures that are difficult to control and are associated to delayed neuropsychomotor development, which results in a deterioration in the patient’s quality of life as well as in that of his or her family.AIM: To evaluate the use of cannabidiol as adjuvant therapy in patients with refractory epilepsies.PATIENTS AND METHODS: An observational study was conducted by means of a survey addressed to the patient’s caregiver. Data collected included information about the patient and the caregiver, changes observed in the seizures, neuropsychological effects, side effects and the family’s overall perception following the use of cannabidiol.RESULTS: The evaluation examined 15 patients with refractory epilepsies, who received cannabidiol over a period ranging from one month to one year. The frequency of seizures decreased in 40% of the patients, 60% of the patients were seen to have control over 50% of their seizures and in 27% of them the seizures disappeared completely. Neurocognitive changes were also reported: behaviour improved in 73%; 60% reported an improvement in language; in 50% sleep improved; 43% reported improvements in eating habits; and 100% said their mood had improved. The overall perception of the illness was that there had been improvements in 73% of respondents. The most common side effects were drowsiness and fatigue.CONCLUSIONS: These results suggest a possible beneficial effect of cannabidiol on the control of seizures and on the improvement of certain neurocognitive aspects in patients with refractory epilepsies.

Database: PubMed

62. Assessing the role of serotonergic receptors in cannabidiol’s anticonvulsant efficacy.

Author(s): Pelz MC; Schoolcraft KD; Larson C; Spring MG; López HH

Source: Epilepsy & behavior : E&B; 2017; vol. 73 ; p. 111-118

Publication Date: 2017

Publication Type(s): Journal Article

PubMedID: 28624721

Available  at Epilepsy & behavior : E&B –  from ClinicalKey

Abstract:Cannabidiol (CBD) is a phytocannabinoid that has demonstrated anticonvulsant efficacy in several animal models of seizure. The current experiment validated CBD’s anticonvulsant effect using the acute pentylenetetrazol (PTZ) model. Furthermore, it tested whether CBD reduces seizure activity by interacting with either the serotonergic 5HT1A or 5HT2A receptor. 120 male adolescent Wistar-Kyoto rats were randomly assigned to 8 treatment groups in two consecutive experiments. In both experiments, subjects received either CBD (100mg/kg) or vehicle 60min prior to seizure testing. In Experiment 1, subjects received either WAY-100635 (1mg/kg), a 5HT1A antagonist, or saline vehicle injection 80min prior to seizure testing. In Experiment 2, subjects received either MDL-100907 (0.3mg/kg), a specific 5HT2A antagonist, or 40% DMSO vehicle 80min prior to seizure testing. 85mg/kg of PTZ was administered to induce seizure, and behavior was recorded for 30min. Seizure behaviors were subsequently coded using a 5-point scale of severity. Across both experiments, subjects in the vehicle control groups exhibited high levels of seizure activity and mortality. In both experiments, CBD treatment significantly attenuated seizure activity. Pre-treatment with either WAY-100635 or MDL-100907 did not block CBD’s anticonvulsant effect. WAY-100635 administration, by itself, also led to a significant attenuation of seizure activity. These results do not support the hypothesis that CBD attenuates seizure activity through activation of the 5HT1A or 5HT2A receptor. While this work further confirms the anticonvulsant efficacy of CBD and supports its application in the treatment of human seizure disorders, additional research on CBD’s mechanism of action must be conducted.

Database: PubMed

63. Quality of Life in Childhood Epilepsy in pediatric patients enrolled in a prospective, open-label clinical study with cannabidiol.

Author(s): Rosenberg EC; Louik J; Conway E; Devinsky O; Friedman D

Source: Epilepsia; 2017; vol. 58 (no. 8); p. e96-e100

Publication Date: 2017

Publication Type(s): Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov’t

PubMedID: 28617940

Available  at Epilepsia –  from IngentaConnect – Open Access

Available  at Epilepsia –  from Wiley

Available  at Epilepsia –  from IngentaConnect

Abstract:Recent clinical trials indicate that cannabidiol (CBD) may reduce seizure frequency in pediatric patients with certain forms of treatment-resistant epilepsy. Many of these patients experience significant impairments in quality of life (QOL) in physical, mental, and social dimensions of health. In this study, we measured the caregiver-reported Quality of Life in Childhood Epilepsy (QOLCE) in a subset of patients enrolled in a prospective, open-label clinical study of CBD. Results from caregivers of 48 patients indicated an 8.2 ± 9.9-point improvement in overall patient QOLCE (p < 0.001) following 12 weeks of CBD. Subscores with improvement included energy/fatigue, memory, control/helplessness, other cognitive functions, social interactions, behavior, and global QOL. These differences were not correlated to changes in seizure frequency or adverse events. The results suggest that CBD may have beneficial effects on patient QOL, distinct from its seizure-reducing effects; however, further studies in placebo-controlled, double-blind trials are necessary to confirm this finding.

Database: PubMed

64. Trial of Cannabidiol for Drug-Resistant Seizures in the Dravet Syndrome.

Author(s): Devinsky O; Cross JH; Laux L; Marsh E; Miller I; Nabbout R; Scheffer IE; Thiele EA; Wright S; Cannabidiol in Dravet Syndrome Study Group

Source: The New England journal of medicine; ; vol. 376 (no. 21); p. 2011-2020

Publication Type(s): Journal Article; Multicenter Study; Randomized Controlled Trial

PubMedID: 28538134

Available  at The New England journal of medicine –  from Massachusetts Medical Society

Available  at The New England journal of medicine –  from ProQuest (Hospital Premium Collection) – NHS Version

Available  at The New England journal of medicine –  from University Hospitals of Derby and Burton NHS Foundation Trust Local Print Collection Print holdings: Latest five years: UHDB – Derby site<br><br>Print holdings: 2000 – 2018: UHDB – Burton site

Available  at The New England journal of medicine –  from Unpaywall

Abstract:BACKGROUND: The Dravet syndrome is a complex childhood epilepsy disorder that is associated with drug-resistant seizures and a high mortality rate. We studied cannabidiol for the treatment of drug-resistant seizures in the Dravet syndrome.METHODS: In this double-blind, placebo-controlled trial, we randomly assigned 120 children and young adults with the Dravet syndrome and drug-resistant seizures to receive either cannabidiol oral solution at a dose of 20 mg per kilogram of body weight per day or placebo, in addition to standard antiepileptic treatment. The primary end point was the change in convulsive-seizure frequency over a 14-week treatment period, as compared with a 4-week baseline period.RESULTS: The median frequency of convulsive seizures per month decreased from 12.4 to 5.9 with cannabidiol, as compared with a decrease from 14.9 to 14.1 with placebo (adjusted median difference between the cannabidiol group and the placebo group in change in seizure frequency, -22.8 percentage points; 95% confidence interval [CI], -41.1 to -5.4; P=0.01). The percentage of patients who had at least a 50% reduction in convulsive-seizure frequency was 43% with cannabidiol and 27% with placebo (odds ratio, 2.00; 95% CI, 0.93 to 4.30; P=0.08). The patient’s overall condition improved by at least one category on the seven-category Caregiver Global Impression of Change scale in 62% of the cannabidiol group as compared with 34% of the placebo group (P=0.02). The frequency of total seizures of all types was significantly reduced with cannabidiol (P=0.03), but there was no significant reduction in nonconvulsive seizures. The percentage of patients who became seizure-free was 5% with cannabidiol and 0% with placebo (P=0.08). Adverse events that occurred more frequently in the cannabidiol group than in the placebo group included diarrhea, vomiting, fatigue, pyrexia, somnolence, and abnormal results on liver-function tests. There were more withdrawals from the trial in the cannabidiol group.CONCLUSIONS: Among patients with the Dravet syndrome, cannabidiol resulted in a greater reduction in convulsive-seizure frequency than placebo and was associated with higher rates of adverse events. (Funded by GW Pharmaceuticals; ClinicalTrials.gov number, NCT02091375 .).

Database: PubMed

65. Cannabidiol in Patients With Intractable Epilepsy Due to TSC: A Possible Medication But Not a Miracle.

Author(s): Nickels K

Source: Epilepsy currents; 2017; vol. 17 (no. 2); p. 91-92

Publication Date: 2017

Publication Type(s): Journal Article; Comment

PubMedID: 28490996

Available  at Epilepsy currents –  from Europe PubMed Central – Open Access

Available  at Epilepsy currents –  from Unpaywall

Database: PubMed

66. Treatment-resistant Lennox-Gastaut syndrome: therapeutic trends, challenges and future directions.

Author(s): Ostendorf AP; Ng YT

Source: Neuropsychiatric disease and treatment; 2017; vol. 13 ; p. 1131-1140

Publication Date: 2017

Publication Type(s): Journal Article; Review

PubMedID: 28461749

Available  at Neuropsychiatric disease and treatment –  from Europe PubMed Central – Open Access

Available  at Neuropsychiatric disease and treatment –  from Unpaywall

Abstract:Lennox-Gastaut syndrome is a severe, childhood-onset electroclinical syndrome comprised of multiple seizure types, intellectual and behavioral disturbances and characteristic findings on electroencephalogram of slow spike and wave complexes and paroxysmal fast frequency activity. Profound morbidity often accompanies a common and severe seizure type, the drop attack. Seizures often remain refractory, or initial treatment efficacy fades. Few individuals are seizure free despite the development of multiple generations of antiseizure medications over decades and high-level evidence on several choices. Approved medications such as lamotrigine, topiramate, rufinamide, felbamate and clobazam have demonstrated efficacy in reducing seizure burden. Cannabidiol has emerged as a promising investigational therapy with vast social interest yet lacks a standard, approved formulation. Palliative surgical procedures, such as vagal nerve stimulation and corpus callosotomy may provide reduction in total seizures and drop attacks. Emerging evidence suggests that complete callosotomy provides greater improvement in seizures without additional side effects. Etiologies such as dysplasia or hypothalamic hamartoma may be amenable for focal resection and thus offer potential to reverse this devastating epileptic encephalopathy.

Database: PubMed

67. Cannabidiol Treatment for Refractory Seizures in Sturge-Weber Syndrome.

Author(s): Kaplan EH; Offermann EA; Sievers JW; Comi AM

Source: Pediatric neurology; Jun 2017; vol. 71 ; p. 18-23.e2

Publication Date: Jun 2017

Publication Type(s): Journal Article

PubMedID: 28454984

Available  at Pediatric neurology –  from ClinicalKey

Abstract:BACKGROUND: Sturge-Weber syndrome results in leptomeningeal vascular malformations, medically refractory epilepsy, stroke(s), and cognitive impairments. Cannabidiol, a cannabinoid without psychoactive properties, has been demonstrated in preclinical models to possibly have anticonvulsant, antioxidant, and neuroprotective actions.METHODS: Five subjects with Sturge-Weber syndrome brain involvement and treatment-resistant epilepsy were enrolled. Motor seizure frequency, quality of life, and adverse events were recorded from the eighth week of the pretreatment period, eight weeks after starting maintenance dose (week 14), and the most recent visit.RESULTS: Four subjects had data through week 14, one of whom initially withdrew for lack of efficacy but because of other benefits re-enrolled with a lower dose. Two subjects at week 14 and three subjects with bilateral brain involvement had at the last visit a greater than 50% seizure reduction, reported an improved quality of life, and remained on cannabidiol 63-80 weeks after starting the drug. Three subjects reported mild side effects considered related to cannabidiol.CONCLUSION: This study suggests that cannabidiol may be well tolerated as adjunctive medication for seizure management and provides initial data supporting further study of cannabidiol in individuals with Sturge-Weber syndrome.

Database: PubMed

68. Neurological Disorders in Medical Use of Cannabis: An Update.

Author(s): Solimini R; Rotolo MC; Pichini S; Pacifici R

Source: CNS & neurological disorders drug targets; 2017; vol. 16 (no. 5); p. 527-533

Publication Date: 2017

Publication Type(s): Journal Article; Review

PubMedID: 28412919

Abstract:BACKGROUND & OBJECTIVE: Medical cannabis is increasingly used as a treatment or adjunct treatment with different levels of efficacy in several neurological disorders or related symptoms (such as multiple sclerosis, autism, Parkinson and Alzheimer disease, Tourette’s syndrome, Huntington’s disease, neuropathic pain, epilepsy, headache), as well as in other medical conditions (e.g. nausea and vomiting, glaucoma, appetite stimulation, cancer, inflammatory conditions, asthma). Nevertheless, a number of neurological adverse effects from use of medical cannabis on the short- and on the longterm have been reported, in addition to other adverse health events.CONCLUSION: It has been noticed that the use of medical cannabis can lead to a paradoxical effects depending on the amount of delta-9-tetrahydrocannabinol (THC) -like cannabinoids the preparation contain. Accordingly, some neurological disorders or symptoms (e.g. multiple sclerosis, seizures, epilepsy, headache) may be caused or exacerbated by the same treatment supposed to cure them. The current review presents an update of the neurological adverse effects resulting from the use of cannabis for medical purposes, highlighting the need to weigh the benefits and risks, when using cannabinoidbased treatments.

Database: PubMed

69. Neurological Aspects of Medical Use of Cannabidiol.

Author(s): Mannucci C; Navarra M; Calapai F; Spagnolo EV; Busardò FP; Cas RD; Ippolito FM; Calapai G

Source: CNS & neurological disorders drug targets; 2017; vol. 16 (no. 5); p. 541-553

Publication Date: 2017

Publication Type(s): Journal Article; Review

PubMedID: 28412918

Available  at CNS & neurological disorders drug targets –  from Unpaywall

Abstract:BACKGROUND: Cannabidiol (CBD) is among the major secondary metabolites of Cannabis devoid of the delta-9-tetra-hydrocannabinol psychoactive effects. It is a resorcinol-based compound with a broad spectrum of potential therapeutic properties, including neuroprotective effects in numerous pathological conditions. CBD neuroprotection is due to its antioxidant and antiinflammatory activities and the modulation of a large number of brain biological targets (receptors, channels) involved in the development and maintenance of neurodegenerative diseases.OBJECTIVE: The aim of the present review was to describe the state of art about the pre-clinical research, the potential use and, when existing, the clinical evidence related to CBD in the neurological field.METHOD: Collection of all the pre-clinical and clinical findings carried out investigating the effects of CBD alone, not in combination with other substances, in the neurological arena with the exclusion of studies on neuropsychiatric disorders.RESULTS: Laboratory and clinical studies on the potential role of CBD in Parkinson’s disease (PD), Alzheimer’s disease (AD), multiple sclerosis (MS), Huntington’s disease (HD), amyotrophic lateral sclerosis ALS), cerebral ischemia, were examined.CONCLUSION: Pre-clinical evidence largely shows that CBD can produce beneficial effects in AD, PD and MS patients, but its employment for these disorders needs further confirmation from well designed clinical studies. CBD pre-clinical demonstration of antiepileptic activity is supported by recent clinical studies in human epileptic subjects resistant to standard antiepileptic drugs showing its potential use in children and young adults affected by refractory epilepsy. Evidence for use of CBD in PD is still not supported by sufficient data whereas only a few studies including a small number of patients are available.

Database: PubMed

70. Report from a Survey of Parents Regarding the Use of Cannabidiol (Medicinal cannabis) in Mexican Children with Refractory Epilepsy.

Author(s): Aguirre-Velázquez CG

Source: Neurology research international; 2017; vol. 2017 ; p. 2985729

Publication Date: 2017

Publication Type(s): Journal Article

PubMedID: 28392943

Available  at Neurology research international –  from Europe PubMed Central – Open Access

Available  at Neurology research international –  from Hindawi Open Access Journals

Available  at Neurology research international –  from Unpaywall

Abstract:Structured online surveys were used to explore the experiences of the parents of children with refractory epilepsy using medicinal cannabis in Mexico during September 2016. The surveys, which were completed in full, were reviewed, and 53 cases of children aged between 9 months and 18 years were identified. Of these, 43 cases (82%) were from Mexico and 10 (18%) were from Latin American countries. Of the 43 Mexican cases, the diagnoses were as follows: 20 cases (47%) had Lennox-Gastaut syndrome (LGS); 13 cases (30%) had unspecified refractory epilepsy (URE); 8 cases (19%) had West syndrome (WS); 1 case (2%) had Doose syndrome (DS); and 1 case (2%) had Ohtahara syndrome (OS). In total, 47.1% of cases had previously been treated with 9 or more anticonvulsant therapies. The parents reported a decrease in convulsions when cannabidiol was used in 81.3% of the cases; a moderate to significant decrease occurred in 51% of cases, and 16% of cases were free from seizure. The number of antiepileptic drugs being used was reduced in 9/43 (20.9%) cases. No serious adverse effects were reported, with only some mild adverse effects, such as increased appetite or changes in sleep patterns, reported in 42% of cases.

Database: PubMed

71. The current status of artisanal cannabis for the treatment of epilepsy in the United States.

Author(s): Sulak D; Saneto R; Goldstein B

Source: Epilepsy & behavior : E&B; 2017; vol. 70 (no. Pt B); p. 328-333

Publication Date: 2017

Publication Type(s): Case Reports; Journal Article; Observational Study

PubMedID: 28254350

Available  at Epilepsy & behavior : E&B –  from ClinicalKey

Abstract:The widespread patient use of artisanal cannabis preparations has preceded quality validation of cannabis use for epilepsy. Neurologists and cannabinoid specialists are increasingly in a position to monitor and guide the use of herbal cannabis in epilepsy patients. We report the retrospective data on efficacy and adverse effects of artisanal cannabis in Patients with medically refractory epilepsy with mixed etiologies in Washington State, California, and Maine. Clinical considerations, including potential risks and benefits, challenges related to artisanal preparations, and cannabinoid dosing, are discussed.RESULTS: Of 272 combined patients from Washington State and California, 37 (14%) found cannabis ineffective at reducing seizures, 29 (15%) experienced a 1-25% reduction in seizures, 60 (18%) experienced a 26-50% reduction in seizures, 45 (17%) experienced a 51-75% reduction in seizures, 75 (28%) experienced a 76-99% reduction in seizures, and 26 (10%) experienced a complete clinical response. Overall, adverse effects were mild and infrequent, and beneficial side effects such as increased alertness were reported. The majority of patients used cannabidiol (CBD)-enriched artisanal formulas, some with the addition of delta-9-tetrahydrocannabinol (THC) and tetrahydrocannabinolic acid (THCA). Four case reports are included that illustrate clinical responses at doses <0.1mg/kg/day, biphasic dose-response effects, the use of THCA for seizure prevention, the use of THC for seizure rescue, and the synergy of cannabinoids and terpenoids in artisanal preparations. This article is part of a Special Issue entitled “Cannabinoids and Epilepsy”.

Database: PubMed

72. An Australian nationwide survey on medicinal cannabis use for epilepsy: History of antiepileptic drug treatment predicts medicinal cannabis use.

Author(s): Suraev AS; Todd L; Bowen MT; Allsop DJ; McGregor IS; Ireland C; Lintzeris N

Source: Epilepsy & behavior : E&B; 2017; vol. 70 (no. Pt B); p. 334-340

Publication Date: 2017

Publication Type(s): Journal Article

PubMedID: 28238865

Available  at Epilepsy & behavior : E&B –  from ClinicalKey

Available  at Epilepsy & behavior : E&B –  from Unpaywall

Abstract:Epilepsy Action Australia conducted an Australian nationwide online survey seeking opinions on and experiences with the use of cannabis-based products for the treatment of epilepsy. The survey was promoted via the Epilepsy Action Australia’s main website, on their Facebook page, and by word of mouth. The survey consisted of 39 questions assessing demographics, clinical factors, including diagnosis and seizure types, and experiences with and opinions towards cannabis use in epilepsy. A total of 976 responses met the inclusion criteria. Results show that 15% of adults with epilepsy and 13% of parents/guardians of children with epilepsy were currently using, or had previously used, cannabis products to treat epilepsy. Of those with a history of cannabis product use, 90% of adults and 71% of parents reported success in reducing seizure frequency after commencing cannabis products. The main reasons for medicinal cannabis use were to manage treatment-resistant epilepsy and to obtain a more favorable side-effect profile compared to standard antiepileptic drugs. The number of past antiepileptic drugs tried was a significant predictor of medicinal cannabis use in both adults and children with epilepsy. Fifty-six percent of adults with epilepsy and 62% of parents/guardians of children with epilepsy expressed willingness to participate in clinical trials of cannabinoids. This survey provides insight into the use of cannabis products for epilepsy, in particular some of the likely factors influencing use, as well as novel insights into the experiences of and attitudes towards medicinal cannabis in people with epilepsy in the Australian community. This article is part of a Special Issue entitled “Cannabinoids and Epilepsy”.

Database: PubMed

73. Social correlates of health status, quality of life, and mood states in patients treated with cannabidiol for epilepsy.

Author(s): Szaflarski M; Hansen B; Bebin EM; Szaflarski JP

Source: Epilepsy & behavior : E&B; 2017; vol. 70 (no. Pt B); p. 364-369

Publication Date: 2017

Publication Type(s): Clinical Trial; Journal Article

PubMedID: 28236578

Available  at Epilepsy & behavior : E&B –  from ClinicalKey

Abstract:Social characteristics, such as socioeconomic status and race/ethnicity, play a role in the treatment and outcomes of patients with epilepsy (PWE), but little is known about how these factors affect patients receiving cannabidiol (CBD) to treat seizures. This exploratory study examined the sociodemographic profile of patients treated with CBD (n=80) and associations between social factors and patient-centered outcomes – overall health status, Quality of Life in Epilepsy-89 (QOLIE-89), and Profile of Mood States (POMS) – in this population. Associations were examined using Pearson correlations and multiple ordinary-least-squares regression (alpha=0.1). The sample was predominantly white (96%) and non-Hispanic/Latino (96%); 76% of patients had family incomes of $40,000+/year. Some patients/families reported experiencing food scarcity (13%), not being able to make ends meet (6%), or not being able to afford antiepileptic medications (8%). The patients’ health ratings declined with age and income (p≤0.014), and there was a statistically significant interaction (p<0.055) between these variables: for example, a higher-income 10-year-old had a predicted health rating of 3 (“very good”), followed by a higher-income 40-year-old with a rating of 2 (“good”), a low-income 10-year-old with a rating of 1 (“fair”), and a low-income 40-year-old with a rating of 0 (“poor”). This is the first study reporting the social profile of patients taking pharmaceutical grade CBD for the treatment of epilepsy. The results suggest that despite free access to this treatment some patients may not be accessing CBD because of their socioeconomic situation or race/ethnicity. Larger, diverse samples and longitudinal data are needed to more accurately model social factors and patient-centered outcomes in PWE receiving CBD. This article is part of a Special Issue entitled “Cannabinoids and Epilepsy”.

Database: PubMed

74. Therapeutic effects of cannabinoids in animal models of seizures, epilepsy, epileptogenesis, and epilepsy-related neuroprotection.

Author(s): Rosenberg EC; Patra PH; Whalley BJ

Source: Epilepsy & behavior : E&B; 2017; vol. 70 (no. Pt B); p. 319-327

Publication Date: 2017

Publication Type(s): Journal Article; Review

PubMedID: 28190698

Available  at Epilepsy & behavior : E&B –  from ClinicalKey

Available  at Epilepsy & behavior : E&B –  from Unpaywall

Abstract:The isolation and identification of the discrete plant cannabinoids in marijuana revived interest in analyzing historical therapeutic claims made for cannabis in clinical case studies and anecdotes. In particular, sources as old as the 11th and 15th centuries claimed efficacy for crude marijuana extracts in the treatment of convulsive disorders, prompting a particularly active area of preclinical research into the therapeutic potential of plant cannabinoids in epilepsy. Since that time, a large body of literature has accumulated describing the effects of several of the >100 individual plant cannabinoids in preclinical models of seizures, epilepsy, epileptogenesis, and epilepsy-related neuroprotection. We surveyed the literature for relevant reports of such plant cannabinoid effects and critically reviewed their findings. We found that acute CB1R agonism in simple models of acute seizures in rodents typically produces anti-convulsant effects whereas CB1R antagonists exert converse effects in the same models. However, when the effects of such ligands are examined in more complex models of epilepsy, epileptogenesis and neuroprotection, a less simplistic narrative emerges. Here, the complex interactions between (i) brain regions involved in a given model, (ii) relative contributions of endocannabinoid signaling to modulation of synaptic transmission in such areas, (iii) multi-target effects, (iv) cannabinoid type 1 and type 2 receptor signaling interactions and, (v) timing, (vi) duration and (vii) localization of ligand administration suggest that there is both anti-epileptic therapeutic potential and a pro-epileptic risk in up- and down-regulation of endocannabinoid signaling in the central nervous system. Factors such receptor desensitization and specific pharmacology of ligands used (e.g. full vs partial agonists and neutral antagonists vs inverse agonists) also appear to play an important role in the effects reported. Furthermore, the effects of several plant cannabinoids, most notably cannabidiol (CBD) and cannabidavarin (CBDV), in models of seizures, epilepsy, epileptogenesis, and neuroprotection are less ambiguous, and consistent with reports of therapeutically beneficial effects of these compounds in clinical studies. However, continued paucity of firm information regarding the therapeutic molecular mechanism of CBD/CBDV highlights the continued need for research in this area in order to identify as yet under-exploited targets for drug development and raise our understanding of treatment-resistant epilepsies. The recent reporting of positive results for cannabidiol treatment in two Phase III clinical trials in treatment-resistant epilepsies provides pivotal evidence of clinical efficacy for one plant cannabinoid in epilepsy. Moreover, risks and/or benefits associated with the use of unlicensed Δ9-THC containing marijuana extracts in pediatric epilepsies remain poorly understood. Therefore, in light of these paradigm-changing clinical events, the present review’s findings aim to drive future drug development for newly-identified targets and indications, identify important limitations of animal models in the investigation of plant cannabinoid effects in the epilepsies, and focuses future research in this area on specific, unanswered questions regarding the complexities of endocannabinoid signaling in epilepsy. This article is part of a Special Issue titled Cannabinoids and Epilepsy.

Database: PubMed

75. Treatment issues for children with epilepsy transitioning to adult care.

Author(s): Nabbout R; Camfield CS; Andrade DM; Arzimanoglou A; Chiron C; Cramer JA; French JA; Kossoff E; Mula M; Camfield PR

Source: Epilepsy & behavior : E&B; 2017; vol. 69 ; p. 153-160

Publication Date: 2017

Publication Type(s): Journal Article; Review

PubMedID: 28188045

Available  at Epilepsy & behavior : E&B –  from ClinicalKey

Abstract:This is the third of three papers that summarize the second symposium on Transition in Epilepsies held in Paris in June 2016. This paper focuses on treatment issues that arise during the course of childhood epilepsy and make the process of transition to adult care more complicated. Some AEDs used during childhood, such as stiripentol, vigabatrin, and cannabidiol, are unfamiliar to adult epilepsy specialists. In addition, new drugs are being developed for treatment of specific childhood onset epilepsy syndromes and have no indication yet for adults. The ketogenic diet may be effective during childhood but is difficult to continue in adult care. Regional adult epilepsy diet clinics could be helpful. Polytherapy is common for patients transitioning to adult care. Although these complex AED regimes are difficult, they are often possible to simplify. AEDs used in childhood may need to be reconsidered in adulthood. Rescue medications to stop prolonged seizures and clusters of seizures are in wide home use in children and can be continued in adulthood. Adherence/compliance is notoriously difficult for adolescents, but there are simple clinical approaches that should be helpful. Mental health issues including depression and anxiety are not always diagnosed and treated in children and young adults even though effective treatments are available. Attention deficit hyperactivity disorder and aggressive behavior disorders may interfere with transition and successful adulthood but these can be treated. For the majority, the adult social outcome of children with epilepsy is unsatisfactory with few proven interventions. The interface between pediatric and adult care for children with epilepsy is becoming increasingly complicated with a need for more comprehensive transition programs and adult epileptologists who are knowledgeable about special treatments that benefit this group of patients.

Database: PubMed

76. Cannabinoids in treatment-resistant epilepsy: A review.

Author(s): O’Connell BK; Gloss D; Devinsky O

Source: Epilepsy & behavior : E&B; 2017; vol. 70 (no. Pt B); p. 341-348

Publication Date: 2017

Publication Type(s): Journal Article; Review

PubMedID: 28188044

Available  at Epilepsy & behavior : E&B –  from ClinicalKey

Abstract:Treatment-resistant epilepsy (TRE) affects 30% of epilepsy patients and is associated with severe morbidity and increased mortality. Cannabis-based therapies have been used to treat epilepsy for millennia, but only in the last few years have we begun to collect data from adequately powered placebo-controlled, randomized trials (RCTs) with cannabidiol (CBD), a cannabis derivative. Previously, information was limited to case reports, small series, and surveys reporting on the use of CBD and diverse medical marijuana (MMJ) preparations containing: tetrahydrocannabinol (THC), CBD, and many other cannabinoids in differing combinations. These RCTs have studied the safety and explored the potential efficacy of CBD use in children with Dravet Syndrome (DS) and Lennox-Gastaut Syndrome (LGS). The role of the placebo response is of paramount importance in studying medical cannabis products given the intense social and traditional media attention, as well as the strong beliefs held by many parents and patients that a natural product is safer and more effective than FDA-approved pharmaceutical agents. We lack valid data on the safety, efficacy, and dosing of artisanal preparations available from dispensaries in the 25 states and District of Columbia with MMJ programs and online sources of CBD and other cannabinoids. On the other hand, open-label studies with 100mg/ml CBD (Epidiolex®, GW Pharmaceuticals) have provided additional evidence of its efficacy along with an adequate safety profile (including certain drug interactions) in children and young adults with a spectrum of TREs. Further, Phase 3 RCTs with Epidiolex support efficacy and adequate safety profiles for children with DS and LGS at doses of 10- and 20-mg/kg/day. This article is part of a Special Issue titled “Cannabinoids and Epilepsy”.

Database: PubMed

77. Are cannabinoids effective for epilepsy?

Author(s): Peña J; Rada G

Source: Medwave; Jan 2017; vol. 17 (no. Suppl1); p. e6821

Publication Date: Jan 2017

Publication Type(s): Journal Article; Meta-Analysis; Review

PubMedID: 28112710

Available  at Medwave –  from Unpaywall

Abstract:Several beneficial effects have been proposed for cannabinoids in different clinical conditions, including epilepsy. However, their clinical role is controversial. Searching in Epistemonikos database, which is maintained by screening multiple databases, we identified five systematic reviews including four randomized trials addressing the question of this article. We extracted data and generated a summary of findings following the GRADE approach. We concluded it is not clear whether cannabinoids reduce the frequency of seizures in epilepsy because the certainty of the evidence is very low, and they probably increase adverse effects.

Database: PubMed

78. Neuroimaging studies towards understanding the central effects of pharmacological cannabis products on patients with epilepsy.

Author(s): Allendorfer JB; Szaflarski JP

Source: Epilepsy & behavior : E&B; 2017; vol. 70 (no. Pt B); p. 349-354

Publication Date: 2017

Publication Type(s): Journal Article; Review

PubMedID: 28109780

Available  at Epilepsy & behavior : E&B –  from ClinicalKey

Abstract:Recent interest for the use of cannabis-derived products as therapeutic agents in the treatment of epilepsies has necessitated a reevaluation of their effects on brain and behavior. Overall, prolonged cannabis use is thought to result in functional and structural brain alterations. These effects may be dependent on a number of factors: e.g., which phytocannabinoid is used (e.g., cannabidiol (CBD) vs. tetrahyrocannabinol (THC)), the frequency of use (occasional vs. heavy), and at what age (prenatal, childhood, adulthood) the use began. However, due to the fact that there are over seven hundred constituents that make up the Cannabis sativa plant, it is difficult to determine which compound or combination of compounds is responsible for specific effects when studying recreational users. Therefore, this review focuses only on the functional MRI studies investigating the effects of specific pharmacological preparations of cannabis compounds, specifically THC, tetrahydrocannabivarin (THCV), and CBD, on brain function in healthy individuals and persons with epilepsy with references to non-epilepsy studies only to underline the gaps in research that need to be filled before cannabis-derived products are considered for a wide use in the treatment of epilepsy. This article is part of a Special Issue entitled “Cannabinoids and Epilepsy”.

Database: PubMed

79. Historical perspective on the medical use of cannabis for epilepsy: Ancient times to the 1980s.

Author(s): Friedman D; Sirven JI

Source: Epilepsy & behavior : E&B; 2017; vol. 70 (no. Pt B); p. 298-301

Publication Date: 2017

Publication Type(s): Historical Article; Journal Article; Review

PubMedID: 28089286

Available  at Epilepsy & behavior : E&B –  from ClinicalKey

Abstract:There has been a dramatic surge in the interest of utilizing cannabis for epilepsy treatment in the US. Yet, access to cannabis for research and therapy is mired in conflicting regulatory policies and shifting public opinion. Understanding the current state of affairs in the medical cannabis debate requires an examination of the history of medical cannabis use. From ancient Chinese pharmacopeias to the current Phase III trials of pharmaceutical grade cannabidiol, this review covers the time span of cannabis use for epilepsy therapy so as to better assess the issues surrounding the modern medical opinion of cannabis use. This article is part of a Special Issue titled Cannabinoids and Epilepsy.

Database: PubMed

80. Pharmacology of cannabinoids in the treatment of epilepsy.

Author(s): Gaston TE; Friedman D

Source: Epilepsy & behavior : E&B; 2017; vol. 70 (no. Pt B); p. 313-318

Publication Date: 2017

Publication Type(s): Journal Article; Review

PubMedID: 28087250

Available  at Epilepsy & behavior : E&B –  from ClinicalKey

Abstract:The use of cannabis products in the treatment of epilepsy has long been of interest to researchers and clinicians alike; however, until recently very little published data were available to support its use. This article summarizes the available scientific data of pharmacology from human and animal studies on the major cannabinoids which have been of interest in the treatment of epilepsy, including ∆9-tetrahydrocannabinol (∆9-THC), cannabidiol (CBD), ∆9-tetrahydrocannabivarin (∆9-THCV), cannabidivarin (CBDV), and ∆9-tetrahydrocannabinolic acid (Δ9-THCA). It has long been known that ∆9-THC has partial agonist activity at the endocannabinoid receptors CB1 and CB2, though it also binds to other targets which may modulate neuronal excitability and neuroinflammation. The actions of Δ9-THCV and Δ9-THCA are less well understood. In contrast to ∆9-THC, CBD has low affinity for CB1 and CB2 receptors and other targets have been investigated to explain its anticonvulsant properties including TRPV1, voltage gated potassium and sodium channels, and GPR55, among others. We describe the absorption, distribution, metabolism, and excretion of each of the above mentioned compounds. Cannabinoids as a whole are very lipophilic, resulting in decreased bioavailability, which presents challenges in optimal drug delivery. Finally, we discuss the limited drug-drug interaction data available on THC and CBD. As cannabinoids and cannabis-based products are studied for efficacy as anticonvulsants, more investigation is needed regarding the specific targets of action, optimal drug delivery, and potential drug-drug interactions. This article is part of a Special Issue titled Cannabinoids and Epilepsy.

Database: PubMed

81. Cannabis and epilepsy: An ancient treatment returns to the fore.

Author(s): Russo EB

Source: Epilepsy & behavior : E&B; 2017; vol. 70 (no. Pt B); p. 292-297

Publication Date: 2017

Publication Type(s): Historical Article; Journal Article; Review

PubMedID: 27989385

Available  at Epilepsy & behavior : E&B –  from ClinicalKey

Abstract:Cannabis has been associated with the treatment of epilepsy throughout history, and if ancient Assyrian sources referring to “hand of ghost” are considered credible, this relationship may span four millennia. A tradition of usage continued in Arabic medicine and Ayurvedic practice in India, which led, in turn, to early experiments in Europe and North America with “Indian hemp.” Lack of standardization, bioavailability issues, and ultimately prohibition were all factors in cannabis-based medicines failing to maintain mainstream usage in seizure treatment, but investigation was resumed in the 1970s with interesting signals noted in both laboratory and clinical settings. Early case studies showed promise, but lacked sufficient rigor. Resumption of research coupled with mass experimentation by families of epilepsy patients has led to intense interest in cannabis-based medicines for its treatment once more, with greatest focus on cannabidiol, but additional investigation of tetrahydrocannabinol, tetrahydrocannabinolic acid, and other phytocannabinoids. This article is part of a Special Issue entitled “Cannabinoids and Epilepsy”.

Database: PubMed

82. Duration of use of oral cannabis extract in a cohort of pediatric epilepsy patients.

Author(s): Treat L; Chapman KE; Colborn KL; Knupp KG

Source: Epilepsia; 2017; vol. 58 (no. 1); p. 123-127

Publication Date: 2017

Publication Type(s): Journal Article

PubMedID: 27859038

Available  at Epilepsia –  from IngentaConnect – Open Access

Available  at Epilepsia –  from Wiley

Available  at Epilepsia –  from IngentaConnect

Abstract:OBJECTIVE: Oral cannabis extracts (OCEs) are being used in the treatment of epilepsy with increasing rates in the United States following product legalization; however, no studies demonstrate clear efficacy. We evaluated the duration of use of OCEs as a measure of perceived benefit in a cohort of patients with pediatric epilepsy.METHODS: Retrospective chart review was performed of children and adolescents who were given OCEs for treatment of epilepsy.RESULTS: Of the 119 patients included in the analysis, 71% terminated use of their OCE product during the study period. The average length of use of OCE was 11.7 months (range 0.3-57 months). Perceived seizure benefit was the only factor associated with longer duration of treatment with OCE (p  50% reduction in seizures while on this therapy. Adverse events (AEs) were reported in 19% of patients, with the most common side effects being somnolence and worsening of seizures.SIGNIFICANCE: Parental report of OCE use in refractory pediatric epilepsy suggests that some families perceive benefit from this therapy; however, discontinuation of these products is common. Duration appears to be affected by logical factors, such as perceived benefit and side effect profile. Surprisingly, families of patients with Dravet syndrome terminated use of OCEs more quickly than patients with other epilepsy syndromes. Results from this study highlight the need for rigorous clinical studies to characterize the efficacy and safety of OCEs, which can inform discussions with patients and families.

Database: PubMed

83. Δ9-THC Intoxication by Cannabidiol-Enriched Cannabis Extract in Two Children with Refractory Epilepsy: Full Remission after Switching to Purified Cannabidiol.

Author(s): Crippa JA; Crippa AC; Hallak JE; Martín-Santos R; Zuardi AW

Source: Frontiers in pharmacology; 2016; vol. 7 ; p. 359

Publication Date: 2016

Publication Type(s): Journal Article

PubMedID: 27746737

Available  at Frontiers in pharmacology –  from Europe PubMed Central – Open Access

Available  at Frontiers in pharmacology –  from Unpaywall

Abstract:Animal studies and preliminary clinical trials have shown that cannabidiol (CBD)-enriched extracts may have beneficial effects for children with treatment-resistant epilepsy. However, these compounds are not yet registered as medicines by regulatory agencies. We describe the cases of two children with treatment-resistant epilepsy (Case A with left frontal dysplasia and Case B with Dravet Syndrome) with initial symptom improvement after the introduction of CBD extracts followed by seizure worsening after a short time. The children presented typical signs of intoxication by Δ9-THC (inappropriate laughter, ataxia, reduced attention, and eye redness) after using a CBD-enriched extract. The extract was replaced by the same dose of purified CBD with no Δ9-THC in both cases, which led to improvement in intoxication signs and seizure remission. These cases support pre-clinical and preliminary clinical evidence suggesting that CBD may be effective for some patients with epilepsy. Moreover, the cases highlight the need for randomized clinical trials using high-quality and reliable substances to ascertain the safety and efficacy of cannabinoids as medicines.

Database: PubMed

84. Cannabidiol as a new treatment for drug-resistant epilepsy in tuberous sclerosis complex.

Author(s): Hess EJ; Moody KA; Geffrey AL; Pollack SF; Skirvin LA; Bruno PL; Paolini JL; Thiele EA

Source: Epilepsia; Oct 2016; vol. 57 (no. 10); p. 1617-1624

Publication Date: Oct 2016

Publication Type(s): Journal Article

PubMedID: 27696387

Available  at Epilepsia –  from IngentaConnect – Open Access

Available  at Epilepsia –  from Wiley

Available  at Epilepsia –  from IngentaConnect

Abstract:OBJECTIVE: Tuberous sclerosis complex (TSC) is an autosomal-dominant genetic disorder with highly variable expression. The most common neurologic manifestation of TSC is epilepsy, which affects approximately 85% of patients, 63% of whom develop treatment-resistant epilepsy. Herein, we evaluate the efficacy, safety, and tolerability of cannabidiol (CBD), a nonpsychoactive compound derived from the marijuana plant, as an adjunct to current antiepileptic drugs in patients with refractory seizures in the setting of TSC.METHODS: Eighteen of the 56 patients who have enrolled in our current expanded-access study of cannabidiol for patients with treatment-resistant epilepsy carry a diagnosis of TSC. After an initial baseline period of 1 month, patients began treatment with CBD. The initial dose of 5 mg/kg/day was increased by 5 mg/kg/day every week up to a maximum dose of 50 mg/kg/day, if tolerated. Weekly seizure frequencies, percent change in seizure frequencies, and responder rates were calculated during the 2nd, 3rd, 6th, 9th, and 12th month of treatment with CBD.RESULTS: The median weekly seizure frequency during the baseline period was 22.0 (interquartile range [IQR] 14.8-57.4), which decreased to 13.3 (IQR 5.1-22.1) after 3 months of treatment with cannabidiol. The median percent change in total weekly seizure frequency was -48.8% (IQR -69.1% to -11.1%) after 3 months of treatment. The 50% responder rates over the course of the study were 50%, 50%, 38.9%, 50%, and 50% after 2, 3, 6, 9, and 12 months of treatment with CBD, respectively. In patients taking clobazam concurrently with CBD (n = 12), the responder rate after 3 months of treatment was 58.3%, compared to 33.3% in patients not taking clobazam (n = 6). Twelve (66.7%) of 18 patients in this study experienced at least one adverse event thought possibly related to CBD; the most common adverse events were drowsiness (n = 8, 44.4%), ataxia (n = 5, 27.8%), and diarrhea (n = 4, 22.2%).SIGNIFICANCE: Although double-blind, placebo-controlled trials are still necessary, these findings suggest that cannabidiol may be an effective and well-tolerated treatment option for patients with refractory seizures in TSC.

Database: PubMed

85. Cannabidiol as a Potential Treatment for Febrile Infection-Related Epilepsy Syndrome (FIRES) in the Acute and Chronic Phases.

Author(s): Gofshteyn JS; Wilfong A; Devinsky O; Bluvstein J; Charuta J; Ciliberto MA; Laux L; Marsh ED

Source: Journal of child neurology; 2017; vol. 32 (no. 1); p. 35-40

Publication Date: 2017

Publication Type(s): Journal Article; Multicenter Study; Research Support, Non-U.S. Gov’t

PubMedID: 27655472

Available  at Journal of child neurology –  from ProQuest (Hospital Premium Collection) – NHS Version

Available  at Journal of child neurology –  from Unpaywall

Abstract:Febrile infection-related epilepsy syndrome (FIRES) is a devastating epilepsy affecting normal children after a febrile illness. FIRES presents with an acute phase with super-refractory status epilepticus and all patients progress to a chronic phase with persistent refractory epilepsy. The typical outcome is severe encephalopathy or death. The authors present 7 children from 5 centers with FIRES who had not responded to antiepileptic drugs or other therapies who were given cannabadiol (Epidiolex, GW Pharma) on emergency or expanded investigational protocols in either the acute or chronic phase of illness. After starting cannabidiol, 6 of 7 patients’ seizures improved in frequency and duration. One patient died due to multiorgan failure secondary to isoflourane. An average of 4 antiepileptic drugs were weaned. Currently 5 subjects are ambulatory, 1 walks with assistance, and 4 are verbal. While this is an open-label case series, the authors add cannabidiol as a possible treatment for FIRES.

Database: PubMed

86. From Cannabis to Cannabidiol to Treat Epilepsy, Where Are We?

Author(s): Lippiello P; Balestrini S; Leo A; Coppola A; Citraro R; Elia M; Russo E; De Sarro G

Source: Current pharmaceutical design; 2016; vol. 22 (no. 42); p. 6426-6433

Publication Date: 2016

Publication Type(s): Journal Article; Review

PubMedID: 27587196

Abstract:BACKGROUND: Several antiepileptic drugs (AEDs), about 25, are currently clinically available for the treatment of patients with epilepsy. Despite this armamentarium and the many recently introduced AEDs, no major advances have been achieved considering the number of drug resistant patients, while many benefits have been indeed obtained for other clinical outcomes (e.g. better tolerability, less interactions). Cannabinoids have long been studied for their potential therapeutical use and more recently phytocannabinoids have been considered a valuable tool for the treatment of several neurological disorders including epilepsy. Among this wide class, the most studied is cannabidiol (CBD) considering its lack of psychotropic effects and its anticonvulsant properties.OBJECTIVE: Analyse the currently available literature on CBD also in light of other data on phytocannabinoids, reviewing data spanning from the mechanism of action, pharmacokinetic to clinical evidences.RESULTS: Several preclinical studies have tried to understand the mechanism of action of CBD, which still remains largely not understood. CBD has shown significant anticonvulsant effects mainly in acute animal models of seizures; beneficial effects were reported also in animal models of epileptogenesis and chronic models of epilepsy, although not substantial. In contrast, data coming from some studies raise questions on the effects of other cannabinoids and above all marijuana.CONCLUSION: There is indeed sufficient supporting data for clinical development and important antiepileptic effects and the currently ongoing clinical studies will permit the real usefulness of CBD and possibly other cannabinoids. Undoubtedly, several issues also need to be addressed in the next future (e.g. better pharmacokinetic profiling). Finally, shading light on the mechanism of action and the study of other cannabinoids might represent an advantage for future developments.

Database: PubMed

87. The Utility of Cannabidiol in the Treatment of Refractory Epilepsy.

Author(s): Reddy DS

Source: Clinical pharmacology and therapeutics; Feb 2017; vol. 101 (no. 2); p. 182-184

Publication Date: Feb 2017

Publication Type(s): Journal Article; Review

PubMedID: 27506704

Abstract:Cannabis-derived cannabinoids such as cannabidiol (CBD) have anticonvulsant properties. Recently, there has been an emerging interest in the use of CBD-enriched products for treatment of drug-resistant epilepsy. Some pilot trials of CBD have proved beneficial for refractory epilepsy, but its efficacy is yet to be confirmed by standard placebo-controlled trials. However, the mechanisms underlying the seizure protection efficacy claims of CBD remain unclear. This review briefly describes the clinical utility of CBD in the treatment of refractory epilepsy.

Database: PubMed

88. Cannabidiol and epilepsy: Rationale and therapeutic potential.

Author(s): Leo A; Russo E; Elia M

Source: Pharmacological research; May 2016; vol. 107 ; p. 85-92

Publication Date: May 2016

Publication Type(s): Journal Article; Review

PubMedID: 26976797

Abstract:Despite the introduction of new antiepileptic drugs (AEDs), the quality of life and therapeutic response for patients with epilepsy remains still poor. Unfortunately, besides several advantages, these new AEDs have not satisfactorily reduced the number of refractory patients. Therefore, the need for different other therapeutic options to manage epilepsy is still a current issue. To this purpose, emphasis has been given to phytocannabinoids, which have been medicinally used since ancient time in the treatment of neurological disorders including epilepsy. In particular, the nonpsychoactive compound cannabidiol (CBD) has shown anticonvulsant properties, both in preclinical and clinical studies, with a yet not completely clarified mechanism of action. However, it should be made clear that most phytocannabinoids do not act on the endocannabinoid system as in the case of CBD. In in vivo preclinical studies, CBD has shown significant anticonvulsant effects mainly in acute animal models of seizures, whereas restricted data exist in chronic models of epilepsy as well as in animal models of epileptogenesis. Likewise, clinical evidence seems to indicate that CBD is able to manage epilepsy both in adults and children affected by refractory seizures, with a favourable side effect profile. However, to date, clinical trials are both qualitatively and numerically limited, thus yet inconsistent. Therefore, further preclinical and clinical studies are undoubtedly needed to better evaluate the potential therapeutic profile of CBD in epilepsy, although the actually available data is promising.

Database: PubMed

89. Is the medical use of cannabis a therapeutic option for children?

Author(s): Rieder MJ; Canadian Paediatric Society, Drug Therapy and Hazardous Substances Committee

Source: Paediatrics & child health; 2016; vol. 21 (no. 1); p. 31-34

Publication Date: 2016

Publication Type(s): Journal Article

PubMedID: 26941559

Available  at Paediatrics & child health –  from ProQuest (Hospital Premium Collection) – NHS Version

Available  at Paediatrics & child health –  from Europe PubMed Central – Open Access

Available  at Paediatrics & child health –  from PubMed

Available  at Paediatrics & child health –  from Unpaywall

Abstract:Cannabis is a psychoactive compound with a long history of recreational and therapeutic use. Current considerations regarding cannabis use for medical purposes in children have been stimulated by recent case reports describing its beneficial effect with refractory epilepsy. Overall, there are insufficient data to support either the efficacy or safety of cannabis use for any indications in children, and an increasing body of data suggests possible harm, most importantly in specific conditions. The potential for cannabis as a therapeutic agent must be evaluated carefully for both efficacy and safety in treating specific paediatric health conditions. Smoking is not an acceptable mode of drug delivery for children. The use of cannabis for medical purposes in specific cases should not be construed as a justification for recreational cannabis use by adolescents. Recommendations for therapeutic use in exceptional paediatric cases are offered, always providing that this treatment course is carefully evaluated in individuals and in ongoing, well-designed research studies to determine safety and efficacy.

Database: PubMed

90. Plant-Derived and Endogenous Cannabinoids in Epilepsy.

Author(s): Verrotti A; Castagnino M; Maccarrone M; Fezza F

Source: Clinical drug investigation; May 2016; vol. 36 (no. 5); p. 331-340

Publication Date: May 2016

Publication Type(s): Journal Article; Review

PubMedID: 26892745

Available  at Clinical drug investigation –  from ProQuest (Hospital Premium Collection) – NHS Version

Abstract:Cannabis is one of the oldest psychotropic drugs and its anticonvulsant properties have been known since the last century. The aim of this review was to analyze the efficacy of cannabis in the treatment of epilepsy in adults and children. In addition, a description of the involvement of the endocannabinoid system in epilepsy is given in order to provide a biochemical background to the effects of endogenous cannabinoids in our body. General tolerability and adverse events associated with cannabis treatment are also investigated. Several anecdotal reports and clinical trials suggest that in the human population cannabis has anticonvulsant properties and could be effective in treating partial epilepsies and generalized tonic-clonic seizures, still known as “grand mal.” They are based, among other factors, on the observation that in individuals who smoke marijuana to treat epilepsy, cessation of cannabis use precipitates the re-emergence of convulsive seizures, whereas resuming consumption of this psychotropic drug controls epilepsy in a reproducible manner. In conclusion, there is some anecdotal evidence for the potential efficacy of cannabis in treating epilepsy. Though there has been an increased effort by patients with epilepsy, their caregivers, growers, and legislators to legalize various forms of cannabis, there is still concern about its efficacy, relative potency, availability of medication-grade preparations, dosing, and potential short- and long-term side effects, including those on prenatal and childhood development.

Database: PubMed

91. Cannabinoids for pediatric epilepsy? Up in smoke or real science?

Author(s): Filloux FM

Source: Translational pediatrics; Oct 2015; vol. 4 (no. 4); p. 271-282

Publication Date: Oct 2015

Publication Type(s): Journal Article; Review

PubMedID: 26835389

Available  at Translational pediatrics –  from Europe PubMed Central – Open Access

Abstract:Public interest in the use of “medical marijuana” for the treatment of childhood epilepsy has burgeoned in the last few years. This has occurred in parallel with a growing interest in “medical marijuana” in general. Physicians and pediatricians must balance their patients’ desire for immediate access to these products with the tenets of evidence-based medicine. This review discusses the biochemistry of cannabis products (the phytocannabinoids) setting this in the context of the endogenous endocannabinoid system. The differing and potentially modulating effects of delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) are reviewed. The evidence-base supporting or not the use of cannabis products for the treatment of neurological disease and specifically epilepsy is explored. The potential for adverse effects and particularly of neurotoxicity is addressed. Finally, public health and sociocultural implications are touched upon. Specific recommendations for interested physicians are provided including advocacy for patients and for a change in the “scheduling” of cannabis in order to better foster much-needed high-quality scientific research in this important area.

Database: PubMed

92. CBD-enriched medical cannabis for intractable pediatric epilepsy: The current Israeli experience.

Author(s): Tzadok M; Uliel-Siboni S; Linder I; Kramer U; Epstein O; Menascu S; Nissenkorn A; Yosef OB; Hyman E; Granot D; Dor M; Lerman-Sagie T; Ben-Zeev B

Source: Seizure; Feb 2016; vol. 35 ; p. 41-44

Publication Date: Feb 2016

Publication Type(s): Journal Article

PubMedID: 26800377

Available  at Seizure –  from ClinicalKey

Available  at Seizure –  from Unpaywall

Abstract:PURPOSE: To describe the experience of five Israeli pediatric epilepsy clinics treating children and adolescents diagnosed as having intractable epilepsy with a regimen of medical cannabis oil.METHODS: A retrospective study describing the effect of cannabidiol (CBD)-enriched medical cannabis on children with epilepsy. The cohort included 74 patients (age range 1-18 years) with intractable epilepsy resistant to >7 antiepileptic drugs. Forty-nine (66%) also failed a ketogenic diet, vagal nerve stimulator implantation, or both. They all started medical cannabis oil treatment between 2-11/2014 and were treated for at least 3 months (average 6 months). The selected formula contained CBD and tetrahydrocannabinol at a ratio of 20:1 dissolved in olive oil. The CBD dose ranged from 1 to 20mg/kg/d. Seizure frequency was assessed by parental report during clinical visits.RESULTS: CBD treatment yielded a significant positive effect on seizure load. Most of the children (66/74, 89%) reported reduction in seizure frequency: 13 (18%) reported 75-100% reduction, 25 (34%) reported 50-75% reduction, 9 (12%) reported 25-50% reduction, and 19 (26%) reported <25% reduction. Five (7%) patients reported aggravation of seizures which led to CBD withdrawal. In addition, we observed improvement in behavior and alertness, language, communication, motor skills and sleep. Adverse reactions included somnolence, fatigue, gastrointestinal disturbances and irritability leading to withdrawal of cannabis use in 5 patients.CONCLUSIONS: The results of this multicenter study on CBD treatment for intractable epilepsy in a population of children and adolescents are highly promising. Further prospective, well-designed clinical trials using enriched CBD medical cannabis are warranted.

Database: PubMed

93. The Pharmacological Basis of Cannabis Therapy for Epilepsy.

Author(s): Reddy DS; Golub VM

Source: The Journal of pharmacology and experimental therapeutics; Apr 2016; vol. 357 (no. 1); p. 45-55

Publication Date: Apr 2016

Publication Type(s): Journal Article; Review

PubMedID: 26787773

Available  at The Journal of pharmacology and experimental therapeutics –  from HighWire – Free Full Text

Available  at The Journal of pharmacology and experimental therapeutics –  from Unpaywall

Abstract:Recently, cannabis has been suggested as a potential alternative therapy for refractory epilepsy, which affects 30% of epilepsy, both adults and children, who do not respond to current medications. There is a large unmet medical need for new antiepileptics that would not interfere with normal function in patients with refractory epilepsy and conditions associated with refractory seizures. The two chief cannabinoids are Δ-9-tetrahyrdrocannabinol, the major psychoactive component of marijuana, and cannabidiol (CBD), the major nonpsychoactive component of marijuana. Claims of clinical efficacy in epilepsy of CBD-predominant cannabis or medical marijuana come mostly from limited studies, surveys, or case reports. However, the mechanisms underlying the antiepileptic efficacy of cannabis remain unclear. This article highlights the pharmacological basis of cannabis therapy, with an emphasis on the endocannabinoid mechanisms underlying the emerging neurotherapeutics of CBD in epilepsy. CBD is anticonvulsant, but it has a low affinity for the cannabinoid receptors CB1 and CB2; therefore the exact mechanism by which it affects seizures remains poorly understood. A rigorous clinical evaluation of pharmaceutical CBD products is needed to establish the safety and efficacy of their use in the treatment of epilepsy. Identification of mechanisms underlying the anticonvulsant efficacy of CBD is also critical for identifying other potential treatment options.

Database: PubMed

94. Cannabidiol in patients with treatment-resistant epilepsy: an open-label interventional trial.

Author(s): Devinsky O; Marsh E; Friedman D; Thiele E; Laux L; Sullivan J; Miller I; Flamini R; Wilfong A; Filloux F; Wong M; Tilton N; Bruno P; Bluvstein J; Hedlund J; Kamens R; Maclean J; Nangia S; Singhal NS; Wilson CA; Patel A; Cilio MR

Source: The Lancet. Neurology; Mar 2016; vol. 15 (no. 3); p. 270-278

Publication Date: Mar 2016

Publication Type(s): Clinical Trial; Journal Article; Multicenter Study; Research Support, Non-U.S. Gov’t

PubMedID: 26724101

Available  at The Lancet. Neurology –  from ClinicalKey

Available  at The Lancet. Neurology –  from ProQuest (Hospital Premium Collection) – NHS Version

Abstract:BACKGROUND: Almost a third of patients with epilepsy have a treatment-resistant form, which is associated with severe morbidity and increased mortality. Cannabis-based treatments for epilepsy have generated much interest, but scientific data are scarce. We aimed to establish whether addition of cannabidiol to existing anti-epileptic regimens would be safe, tolerated, and efficacious in children and young adults with treatment-resistant epilepsy.METHODS: In this open-label trial, patients (aged 1-30 years) with severe, intractable, childhood-onset, treatment-resistant epilepsy, who were receiving stable doses of antiepileptic drugs before study entry, were enrolled in an expanded-access programme at 11 epilepsy centres across the USA. Patients were given oral cannabidiol at 2-5 mg/kg per day, up-titrated until intolerance or to a maximum dose of 25 mg/kg or 50 mg/kg per day (dependent on study site). The primary objective was to establish the safety and tolerability of cannabidiol and the primary efficacy endpoint was median percentage change in the mean monthly frequency of motor seizures at 12 weeks. The efficacy analysis was by modified intention to treat. Comparisons of the percentage change in frequency of motor seizures were done with a Mann-Whitney U test.RESULTS: Between Jan 15, 2014, and Jan 15, 2015, 214 patients were enrolled; 162 (76%) patients who had at least 12 weeks of follow-up after the first dose of cannabidiol were included in the safety and tolerability analysis, and 137 (64%) patients were included in the efficacy analysis. In the safety group, 33 (20%) patients had Dravet syndrome and 31 (19%) patients had Lennox-Gastaut syndrome. The remaining patients had intractable epilepsies of different causes and type. Adverse events were reported in 128 (79%) of the 162 patients within the safety group. Adverse events reported in more than 10% of patients were somnolence (n=41 [25%]), decreased appetite (n=31 [19%]), diarrhoea (n=31 [19%]), fatigue (n=21 [13%]), and convulsion (n=18 [11%]). Five (3%) patients discontinued treatment because of an adverse event. Serious adverse events were reported in 48 (30%) patients, including one death-a sudden unexpected death in epilepsy regarded as unrelated to study drug. 20 (12%) patients had severe adverse events possibly related to cannabidiol use, the most common of which was status epilepticus (n=9 [6%]). The median monthly frequency of motor seizures was 30.0 (IQR 11.0-96.0) at baseline and 15.8 (5.6-57.6) over the 12 week treatment period. The median reduction in monthly motor seizures was 36.5% (IQR 0-64.7).INTERPRETATION: Our findings suggest that cannabidiol might reduce seizure frequency and might have an adequate safety profile in children and young adults with highly treatment-resistant epilepsy. Randomised controlled trials are warranted to characterise the safety profile and true efficacy of this compound.FUNDING: GW Pharmaceuticals, Epilepsy Therapy Project of the Epilepsy Foundation, Finding A Cure for Epilepsy and Seizures.

Database: PubMed

95. Cannabidiol as potential treatment in refractory pediatric epilepsy.

Author(s): Paolino MC; Ferretti A; Papetti L; Villa MP; Parisi P

Source: Expert review of neurotherapeutics; 2016; vol. 16 (no. 1); p. 17-21

Publication Date: 2016

Publication Type(s): Journal Article; Review

PubMedID: 26567560

Abstract:In recent years there has been great scientific and public interest focused on the therapeutic potential of compounds derived from cannabis for the treatment of refractory epilepsy in children. From in vitro and in vivo studies on animal models, cannabidiol (CBD) appears to be a promising anticonvulsant drug with a favorable side-effect profile. In humans, CBD efficacy and safety is not supported by well-designed trials and its use has been described by anecdotal reports. It will be necessary to investigate CBD safety, pharmacokinetics and interaction with other anti-epileptic drugs (AEDs) alongside performing double-blinded placebo-controlled trials in order to obtain conclusive data on its efficacy and safety in children.

Database: PubMed

96. TRPV1 Channel: A Potential Drug Target for Treating Epilepsy.

Author(s): Nazıroğlu M

Source: Current neuropharmacology; 2015; vol. 13 (no. 2); p. 239-247

Publication Date: 2015

Publication Type(s): Journal Article; Review

PubMedID: 26411767

Available  at Current neuropharmacology –  from Europe PubMed Central – Open Access

Available  at Current neuropharmacology –  from PubMed

Available  at Current neuropharmacology –  from Unpaywall

Abstract:Epilepsy has 2-3% incidence worldwide. However, present antiepileptic drugs provide only partial control of seizures. Calcium ion accumulation in hippocampal neurons has long been known as a major contributor to the etiology of epilepsy. TRPV1 is a calcium-permeable channel and mediator of epilepsy in the hippocampus. TRPV1 is expressed in epileptic brain areas such as CA1 area and dentate gyrus of the hippocampus. Here the author reviews the patent literature on novel molecules targeting TRPV1 that are currently being investigated in the laboratory and are candidates for future clinical evaluation in the management of epilepsy. A limited number of recent reports have implicated TRPV1 in the induction or treatment of epilepsy suggesting that this may be new area for potential drugs targeting this debilitating disease. Thus activation of TRPV1 by oxidative stress, resiniferatoxin, cannabinoid receptor (CB1) activators (i.e. anandamide) or capsaicin induced epileptic effects, and these effects could be reduced by appropriate inhibitors, including capsazepine (CPZ), 5′-iodoresiniferatoxin (IRTX), resolvins, and CB1 antagonists. It has been also reported that CPZ and IRTX reduced spontaneous excitatory synaptic transmission through modulation of glutaminergic systems and desensitization of TRPV1 channels in the hippocampus of rats. Immunocytochemical studies indicated that TRPV1 channel expression increased in the hippocampus of mice and patients with temporal lobe epilepsy. Taken together, findings in the current literature support a role for calcium ion accumulation through TRPV1 channels in the etiology of epileptic seizures, indicating that inhibition of TRPV1 in the hippocampus may possibly be a novel target for prevention of epileptic seizures.

Database: PubMed

97. Cannabis and Endocannabinoid Signaling in Epilepsy.

Author(s): Katona I

Source: Handbook of experimental pharmacology; 2015; vol. 231 ; p. 285-316

Publication Date: 2015

Publication Type(s): Journal Article; Research Support, Non-U.S. Gov’t; Review

PubMedID: 26408165

Abstract:The antiepileptic potential of Cannabis sativa preparations has been historically recognized. Recent changes in legal restrictions and new well-documented cases reporting remarkably strong beneficial effects have triggered an upsurge in exploiting medical marijuana in patients with refractory epilepsy. Parallel research efforts in the last decade have uncovered the fundamental role of the endogenous cannabinoid system in controlling neuronal network excitability raising hopes for cannabinoid-based therapeutic approaches. However, emerging data show that patient responsiveness varies substantially, and that cannabis administration may sometimes even exacerbate seizures. Qualitative and quantitative chemical variability in cannabis products and personal differences in the etiology of seizures, or in the pathological reorganization of epileptic networks, can all contribute to divergent patient responses. Thus, the consensus view in the neurologist community is that drugs modifying the activity of the endocannabinoid system should first be tested in clinical trials to establish efficacy, safety, dosing, and proper indication in specific forms of epilepsies. To support translation from anecdote-based practice to evidence-based therapy, the present review first introduces current preclinical and clinical efforts for cannabinoid- or endocannabinoid-based epilepsy treatments. Next, recent advances in our knowledge of how endocannabinoid signaling limits abnormal network activity as a central component of the synaptic circuit-breaker system will be reviewed to provide a framework for the underlying neurobiological mechanisms of the beneficial and adverse effects. Finally, accumulating evidence demonstrating robust synapse-specific pathophysiological plasticity of endocannabinoid signaling in epileptic networks will be summarized to gain better understanding of how and when pharmacological interventions may have therapeutic relevance.

Database: PubMed

98. Marijuana Use in Epilepsy: The Myth and the Reality.

Author(s): Detyniecki K; Hirsch L

Source: Current neurology and neuroscience reports; Oct 2015; vol. 15 (no. 10); p. 65

Publication Date: Oct 2015

Publication Type(s): Journal Article; Review

PubMedID: 26299273

Available  at Current neurology and neuroscience reports –  from ProQuest (Hospital Premium Collection) – NHS Version

Available  at Current neurology and neuroscience reports –  from EBSCO (MEDLINE Complete)

Abstract:Marijuana has been utilized as a medicinal plant to treat a variety of conditions for nearly five millennia. Over the past few years, there has been an unprecedented interest in using cannabis extracts to treat epilepsy, spurred on by a few refractory pediatric cases featured in the media that had an almost miraculous response to cannabidiol-enriched marijuana extracts. This review attempts to answer the most important questions a clinician may have regarding the use of marijuana in epilepsy. First, we review the preclinical and human evidences for the anticonvulsant properties of the different cannabinoids, mainly tetrahydrocannabinol (THC) and cannabidiol (CBD). Then, we explore the safety data from animal and human studies. Lastly, we attempt to reconcile the controversy regarding physicians’ and patients’ opinions about whether the available evidence is sufficient to recommend the use of marijuana to treat epilepsy.

Database: PubMed

99. Cannabinoids and Epilepsy.

Author(s): Rosenberg EC; Tsien RW; Whalley BJ; Devinsky O

Source: Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics; Oct 2015; vol. 12 (no. 4); p. 747-768

Publication Date: Oct 2015

Publication Type(s): Journal Article; Research Support, N.I.H., Extramural; Review

PubMedID: 26282273

Available  at Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics –  from ProQuest (Hospital Premium Collection) – NHS Version

Available  at Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics –  from Europe PubMed Central – Open Access

Available  at Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics –  from EBSCO (MEDLINE Complete)

Available  at Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics –  from Unpaywall

Abstract:Cannabis has been used for centuries to treat seizures. Recent anecdotal reports, accumulating animal model data, and mechanistic insights have raised interest in cannabis-based antiepileptic therapies. In this study, we review current understanding of the endocannabinoid system, characterize the pro- and anticonvulsive effects of cannabinoids [e.g., Δ9-tetrahydrocannabinol and cannabidiol (CBD)], and highlight scientific evidence from pre-clinical and clinical trials of cannabinoids in epilepsy. These studies suggest that CBD avoids the psychoactive effects of the endocannabinoid system to provide a well-tolerated, promising therapeutic for the treatment of seizures, while whole-plant cannabis can both contribute to and reduce seizures. Finally, we discuss results from a new multicenter, open-label study using CBD in a population with treatment-resistant epilepsy. In all, we seek to evaluate our current understanding of cannabinoids in epilepsy and guide future basic science and clinical studies.

Database: PubMed

100. Cannabinoids: is there a potential treatment role in epilepsy?

Author(s): Blair RE; Deshpande LS; DeLorenzo RJ

Source: Expert opinion on pharmacotherapy; 2015; vol. 16 (no. 13); p. 1911-1914

Publication Date: 2015

Publication Type(s): Journal Article; Research Support, N.I.H., Extramural

PubMedID: 26234319

Available  at Expert opinion on pharmacotherapy –  from Unpaywall

Abstract:Cannabinoids have been used medicinally for centuries, and in the last decade, attention has focused on their broad therapeutic potential particularly in seizure management. While some cannabinoids have demonstrated anticonvulsant activity in experimental studies, their efficacy for managing clinical seizures has not been fully established. This commentary will touch on our understanding of the brain endocannabinoid system’s regulation of synaptic transmission in both physiological and pathophysiological conditions, and review the findings from both experimental and clinical studies on the effectiveness of cannabinoids to suppress epileptic seizures. At present, there is preliminary evidence that non-psychoactive cannabinoids may be useful as anticonvulsants, but additional clinical trials are needed to fully evaluate the efficacy and safety of these compounds for the treatment of epilepsy.

Database: PubMed

101. Drug-drug interaction between clobazam and cannabidiol in children with refractory epilepsy.

Author(s): Geffrey AL; Pollack SF; Bruno PL; Thiele EA

Source: Epilepsia; Aug 2015; vol. 56 (no. 8); p. 1246-1251

Publication Date: Aug 2015

Publication Type(s): Journal Article; Research Support, Non-U.S. Gov’t

PubMedID: 26114620

Available  at Epilepsia –  from IngentaConnect – Open Access

Available  at Epilepsia –  from Wiley

Available  at Epilepsia –  from IngentaConnect

Available  at Epilepsia –  from Unpaywall

Abstract:OBJECTIVE: Under an expanded access investigational new drug (IND) trial, cannabidiol (CBD) is being studied as a possible adjuvant treatment of refractory epilepsy in children. Of the 25 subjects in the trial, 13 were being treated with clobazam (CLB). Because CLB and CBD are both metabolized in the cytochrome P450 (CYP) pathway, we predicted a drug-drug interaction, which we evaluate in this article.METHODS: Thirteen subjects with refractory epilepsy concomitantly taking CLB and CBD under IND 119876 were included in this study. Demographic information was collected for each subject including age, sex, and etiology of seizures, as well as concomitant antiepileptic drugs (AEDs). CLB, N-desmethylclobazam (norclobazam; nCLB), and CBD levels were measured over the course of CBD treatment. CLB doses were recorded at baseline and at weeks 4 and 8 of CBD treatment. Side effects were monitored.RESULTS: We report elevated CLB and nCLB levels in these subjects. The mean (± standard deviation [SD]) increase in CLB levels was 60 ± 80% (95% confidence interval (CI) [-2-91%] at 4 weeks); the mean increase in nCLB levels was 500 ± 300% (95% CI [+90-610%] at 4 weeks). Nine of 13 subjects had a >50% decrease in seizures, corresponding to a responder rate of 70%. The increased CLB and nCLB levels and decreases in seizure frequency occurred even though, over the course of CBD treatment, CLB doses were reduced for 10 (77%) of the 13 subjects. Side effects were reported in 10 (77%) of the 13 subjects, but were alleviated with CLB dose reduction.SIGNIFICANCE: Monitoring of CLB and nCLB levels is necessary for clinical care of patients concomitantly on CLB and CBD. Nonetheless, CBD is a safe and effective treatment of refractory epilepsy in patients receiving CLB treatment.

Database: PubMed

102. Perceived efficacy of cannabidiol-enriched cannabis extracts for treatment of pediatric epilepsy: A potential role for infantile spasms and Lennox-Gastaut syndrome.

Author(s): Hussain SA; Zhou R; Jacobson C; Weng J; Cheng E; Lay J; Hung P; Lerner JT; Sankar R

Source: Epilepsy & behavior : E&B; Jun 2015; vol. 47 ; p. 138-141

Publication Date: Jun 2015

Publication Type(s): Journal Article; Research Support, Non-U.S. Gov’t

PubMedID: 25935511

Available  at Epilepsy & behavior : E&B –  from ClinicalKey

Abstract:There is a great need for safe and effective therapies for treatment of infantile spasms (IS) and Lennox-Gastaut syndrome (LGS). Based on anecdotal reports and limited experience in an open-label trial, cannabidiol (CBD) has received tremendous attention as a potential treatment for pediatric epilepsy, especially Dravet syndrome. However, there is scant evidence of specific utility for treatment of IS and LGS. We sought to document the experiences of children with IS and/or LGS who have been treated with CBD-enriched cannabis preparations. We conducted a brief online survey of parents who administered CBD-enriched cannabis preparations for the treatment of their children’s epilepsy. We specifically recruited parents of children with IS and LGS and focused on perceived efficacy, dosage, and tolerability. Survey respondents included 117 parents of children with epilepsy (including 53 with IS or LGS) who had administered CBD products to their children. Perceived efficacy and tolerability were similar across etiologic subgroups. Eighty-five percent of all parents reported a reduction in seizure frequency, and 14% reported complete seizure freedom. Epilepsy was characterized as highly refractory with median latency from epilepsy onset to CBD initiation of five years, during which the patient’s seizures failed to improve after a median of eight antiseizure medication trials. The median duration and the median dosage of CBD exposure were 6.8 months and 4.3mg/kg/day, respectively. Reported side effects were far less common during CBD exposure, with the exception of increased appetite (30%). A high proportion of respondents reported improvement in sleep (53%), alertness (71%), and mood (63%) during CBD therapy. Although this study suggests a potential role for CBD in the treatment of refractory childhood epilepsy including IS and LGS, it does not represent compelling evidence of efficacy or safety. From a methodological standpoint, this study is extraordinarily vulnerable to participation bias and limited by lack of blinded outcome ascertainment. Appropriately controlled clinical trials are essential to establish efficacy and safety.

Database: PubMed

103. Use of cannabis in severe childhood epilepsy and child protection considerations.

Author(s): Yap M; Easterbrook L; Connors J; Koopmans L

Source: Journal of paediatrics and child health; May 2015; vol. 51 (no. 5); p. 491-496

Publication Date: May 2015

Publication Type(s): Journal Article; Review

PubMedID: 29889339

Available  at Journal of paediatrics and child health –  from Wiley Online Library Medicine and Nursing Collection 2018 – NHS

Abstract:The use of medical cannabis in chronic illness is increasingly investigated, yet little is known about its use in paediatric populations. As child protection clinicians are often asked to provide advice around whether parents’ actions to give medical cannabis to their chronically ill child constitutes harm or risk of harm, a review of the evidence base is required. This systematic review explores the use of cannabis-derived products in children with seizure disorders. While a reduction in seizure activity was observed in some children, included studies were poorly designed and too small to extrapolate reliable conclusions about clinical use. Due to the lack of high-quality evidence, the use of cannabis-derived products is currently not recommended in children with seizure disorders. However, in assessing risk and harm to subject children by child protection physicians in Australia with existing State and Territory legislation, evaluation must occur on a case-to-case basis with each instance considered on its individual merits. Clinical trials addressing drug efficacy and long-term safety of cannabis-derived products are required.

Database: PubMed

104. Pure cannabidiol in the treatment of malignant migrating partial seizures in infancy: a case report.

Author(s): Saade D; Joshi C

Source: Pediatric neurology; May 2015; vol. 52 (no. 5); p. 544-547

Publication Date: May 2015

Publication Type(s): Case Reports; Journal Article

PubMedID: 25882081

Available  at Pediatric neurology –  from ClinicalKey

Abstract:BACKGROUND: Malignant migrating partial seizures in infancy is a devastating pharmacoresistent epileptic encephalopathy of unknown etiology characterized by onset in the first 6 months of life, continuous migrating focal seizures with corresponding multifocal electroencephalographic discharges, developmental deterioration, and early mortality. Recent widespread interest in the nonpsychoactive component of the cannabis plant, cannabidiol, as a potential treatment for refractory devastating epilepsies has led to individual trials initiated by families or physicians in states that have legalized medical marijuana with anecdotal success.PATIENT DESCRIPTION: We describe a now 10-month-old boy with malignant migrating partial seizures in infancy who made developmental gains and demonstrated sustained seizure reduction with the addition of cannabidiol to his antiepileptic regimen.CONCLUSION: This report supports a role for cannabidiol in the treatment of malignant migrating partial seizures in infancy.

Database: PubMed

105. Parental reporting of response to oral cannabis extracts for treatment of refractory epilepsy.

Author(s): Press CA; Knupp KG; Chapman KE

Source: Epilepsy & behavior : E&B; Apr 2015; vol. 45 ; p. 49-52

Publication Date: Apr 2015

Publication Type(s): Journal Article

PubMedID: 25845492

Available  at Epilepsy & behavior : E&B –  from ClinicalKey

Abstract:OBJECTIVE: Oral cannabis extracts (OCEs) have been used in the treatment of epilepsy; however, no studies demonstrate clear efficacy. We report on a cohort of pediatric patients with epilepsy who were given OCE and followed in a single tertiary epilepsy center.METHODS: A retrospective chart review of children and adolescents who were given OCE for treatment of their epilepsy was performed.RESULTS: Seventy-five patients were identified of which 57% reported any improvement in seizure control and 33% reported a >50% reduction in seizures (responders). If the family had moved to CO for OCE treatment, the responder rate was 47% vs. 22% for children who already were in CO. The responder rate varied based on epilepsy syndrome: Dravet 23%, Doose 0%, and Lennox-Gastaut syndrome (LGS) 88.9%. The background EEG of the 8 responders where EEG data were available was not improved. Additional benefits reported included: improved behavior/alertness (33%), improved language (10%), and improved motor skills (10%). Adverse events (AEs) occurred in 44% of patients including increased seizures (13%) and somnolence/fatigue (12%). Rare adverse events included developmental regression, abnormal movements, status epilepticus requiring intubation, and death.SIGNIFICANCE: Our retrospective study of OCE use in pediatric patients with epilepsy demonstrates that some families reported patient improvement with treatment; however, we also found a variety of challenges and possible confounding factors in studying OCE retrospectively in an open-labeled fashion. We strongly support the need for controlled, blinded studies to evaluate the efficacy and safety of OCE for treatment of pediatric epilepsies using accurate seizure counts, formal neurocognitive assessments, as well as EEG as a biomarker. This study provides Class III evidence that OCE is well tolerated by children and adolescents with epilepsy.

Database: PubMed

106. Phytocannabinoids and epilepsy.

Author(s): dos Santos RG; Hallak JE; Leite JP; Zuardi AW; Crippa JA

Source: Journal of clinical pharmacy and therapeutics; Apr 2015; vol. 40 (no. 2); p. 135-143

Publication Date: Apr 2015

Publication Type(s): Journal Article; Review

PubMedID: 25475762

Available  at Journal of clinical pharmacy and therapeutics –  from Wiley Online Library Medicine and Nursing Collection 2018 – NHS

Available  at Journal of clinical pharmacy and therapeutics –  from EBSCO (CINAHL Plus with Full Text)

Available  at Journal of clinical pharmacy and therapeutics –  from EBSCO (MEDLINE Complete)

Available  at Journal of clinical pharmacy and therapeutics –  from Unpaywall

Abstract:WHAT IS KNOWN AND OBJECTIVE: Antiepileptic drugs often produce serious adverse effects, and many patients do not respond to them properly. Phytocannabinoids produce anticonvulsant effects in preclinical and preliminary human studies, and appear to produce fewer adverse effects than available antiepileptic drugs. The present review summarizes studies on the anticonvulsant properties of phytocannabinoids.METHODS: Literature search using the PubMed database to identify studies on phytocannabinoids and epilepsy.RESULTS AND DISCUSSION: Preclinical studies suggest that phytocannabinoids, especially cannabidiol and cannabidivarin, have potent anticonvulsant effects which are mediated by the endocannabinoid system. Human studies are limited in number and quality, but suggest that cannabidiol has anticonvulsant effects in adult and infantile epilepsy and is well tolerated after prolonged administration.WHAT IS NEW AND CONCLUSION: Phytocannabinoids produce anticonvulsant effects through the endocannabinoid system, with few adverse effects. Cannabidiol and cannabidivarin should be tested in randomized, controlled clinical trials, especially in infantile epileptic syndromes.

Database: PubMed

107. Medical marijuana in neurology.

Author(s): Benbadis SR; Sanchez-Ramos J; Bozorg A; Giarratano M; Kalidas K; Katzin L; Robertson D; Vu T; Smith A; Zesiewicz T

Source: Expert review of neurotherapeutics; Dec 2014; vol. 14 (no. 12); p. 1453-1465

Publication Date: Dec 2014

Publication Type(s): Journal Article; Research Support, Non-U.S. Gov’t; Review

PubMedID: 25427150

Abstract:Constituents of the Cannabis plant, cannabinoids, may be of therapeutic value in neurologic diseases. The most abundant cannabinoids are Δ(9)-tetrahydrocannabinol, which possesses psychoactive properties, and cannabidiol, which has no intrinsic psychoactive effects, but exhibits neuroprotective properties in preclinical studies. A small number of high-quality clinical trials support the safety and efficacy of cannabinoids for treatment of spasticity of multiple sclerosis, pain refractory to opioids, glaucoma, nausea and vomiting. Lower level clinical evidence indicates that cannabinoids may be useful for dystonia, tics, tremors, epilepsy, migraine and weight loss. Data are also limited in regards to adverse events and safety. Common nonspecific adverse events are similar to those of other CNS ‘depressants’ and include weakness, mood changes and dizziness. Cannabinoids can have cardiovascular adverse events and, when smoked chronically, may affect pulmonary function. Fatalities are rare even with recreational use. There is a concern about psychological dependence, but physical dependence is less well documented. Cannabis preparations may presently offer an option for compassionate use in severe neurologic diseases, but at this point, only when standard-of-care therapy is ineffective. As more high-quality clinical data are gathered, the therapeutic application of cannabinoids will likely expand.

Database: PubMed

108. Fewer specialists support using medical marijuana and CBD in treating epilepsy patients compared with other medical professionals and patients: result of Epilepsia’s survey.

Author(s): Mathern GW; Beninsig L; Nehlig A

Source: Epilepsia; Jan 2015; vol. 56 (no. 1); p. 1-6

Publication Date: Jan 2015

Publication Type(s): Journal Article

PubMedID: 25413126

Available  at Epilepsia –  from IngentaConnect – Open Access

Available  at Epilepsia –  from Wiley

Available  at Epilepsia –  from IngentaConnect

Available  at Epilepsia –  from Unpaywall

Abstract:OBJECTIVE: From May 20 to September 1 2014, Epilepsia conducted an online survey seeking opinions about the use of medical marijuana and cannabidiol (CBD) for people with epilepsy. This study reports the findings of that poll.METHODS: The survey consisted of eight questions. Four questions asked if there were sufficient safety and efficacy data, whether responders would advise trying medical marijuana in cases of severe refractory epilepsy, and if pharmacologic grade compounds containing CBD should be available. Four questions addressed occupation, geographic region of residence, if responders had read the paper, and if they were International League Against Epilepsy/International Bureau for Epilepsy (ILAE/IBE) members.RESULTS: Of 776 who started or completed the survey, 58% were patients from North America, and 22% were epileptologists and general neurologists from Europe and North America. A minority of epileptologists and general neurologists said that there were sufficient safety (34%) and efficacy (28%) data, and 48% would advise using medical marijuana in severe cases of epilepsy. By comparison, nearly all patients and the public said there were sufficient safety (96%) and efficacy (95%) data, and 98% would recommend medical marijuana in cases of severe epilepsy. General physicians, basic researchers, nurses, and allied health professions sided more with patients, saying that there were sufficient safety (70%) and efficacy (71%) data, and 83% would advise using marijuana in severe cases. A majority (78%) said there should be pharmacologic grade compounds containing CBD, and there were no differences between specialists, general medical personal, and patients and the public.SIGNIFICANCE: This survey indicates that there is a wide disparity in opinion on the use of medical marijuana and CBD in the treatment of people with epilepsy, which varied substantially, with fewer medical specialists supporting its use compared with general medical personal, and patients and the public.

Database: PubMed

109. Seizing an opportunity for the endocannabinoid system.

Author(s): Alger BE

Source: Epilepsy currents; Sep 2014; vol. 14 (no. 5); p. 272-276

Publication Date: Sep 2014

Publication Type(s): Journal Article

PubMedID: 25346637

Available  at Epilepsy currents –  from Europe PubMed Central – Open Access

Available  at Epilepsy currents –  from Unpaywall

Abstract:Exogenous cannabinoids can limit seizures and neurodegeneration, and their actions are largely mimicked by endogenous cannabinoids (endocannabinoids). Endocannabinoids are mobilized by epileptiform activity and in turn influence this activity by inhibiting synaptic transmission; both excitatory and some inhibitory synapses can be suppressed, leading to potentially complex outcomes. Moreover, the endocannabinoid system is not a fixed entity, and its strength can be enhanced or reduced. Endocannabinoids and their receptors are altered by epileptic seizures in ways that can reduce the efficacy of both exogenous and endogenous cannabinoids in sometimes unexpected ways.

Database: PubMed

110. Cannabis, cannabidiol, and epilepsy–from receptors to clinical response.

Author(s): Szaflarski JP; Bebin EM

Source: Epilepsy & behavior : E&B; Dec 2014; vol. 41 ; p. 277-282

Publication Date: Dec 2014

Publication Type(s): Journal Article; Research Support, Non-U.S. Gov’t; Review

PubMedID: 25282526

Available  at Epilepsy & behavior : E&B –  from ClinicalKey

Abstract:Recreational cannabis use in adults with epilepsy is widespread. The use of cannabis for medicinal purposes is also becoming more prevalent. For this purpose, various preparations of cannabis of varying strengths and content are being used. The recent changes in the legal environment have improved the availability of products with high cannabidiol (CBD) and low tetrahydrocannabinol (THC) concentrations. There is some anecdotal evidence of their potential efficacy, but the mechanisms of such action are not entirely clear. Some suspect an existence of synergy or “entourage effect” between CBD and THC. There is strong evidence that THC acts via the cannabinoid receptor CB1. The mechanism of action of CBD is less clear but is likely polypharmacological. The scientific data support the role of the endocannabinoid system in seizure generation, maintenance, and control in animal models of epilepsy. There are clear data for the negative effects of cannabis on the developing and mature brain though these effects appear to be relatively mild in most cases. Further data from well-designed studies are needed regarding short- and long-term efficacy and side effects of CBD or high-CBD/low-THC products for the treatment of seizures and epilepsy in children and adults.

Database: PubMed

111. Nonpsychotropic plant cannabinoids, cannabidivarin (CBDV) and cannabidiol (CBD), activate and desensitize transient receptor potential vanilloid 1 (TRPV1) channels in vitro: potential for the treatment of neuronal hyperexcitability.

Author(s): Iannotti FA; Hill CL; Leo A; Alhusaini A; Soubrane C; Mazzarella E; Russo E; Whalley BJ; Di Marzo V; Stephens GJ

Source: ACS chemical neuroscience; Nov 2014; vol. 5 (no. 11); p. 1131-1141

Publication Date: Nov 2014

Publication Type(s): Journal Article; Research Support, Non-U.S. Gov’t

PubMedID: 25029033

Abstract:Epilepsy is the most common neurological disorder, with over 50 million people worldwide affected. Recent evidence suggests that the transient receptor potential cation channel subfamily V member 1 (TRPV1) may contribute to the onset and progression of some forms of epilepsy. Since the two nonpsychotropic cannabinoids cannabidivarin (CBDV) and cannabidiol (CBD) exert anticonvulsant activity in vivo and produce TRPV1-mediated intracellular calcium elevation in vitro, we evaluated the effects of these two compounds on TRPV1 channel activation and desensitization and in an in vitro model of epileptiform activity. Patch clamp analysis in transfected HEK293 cells demonstrated that CBD and CBDV dose-dependently activate and rapidly desensitize TRPV1, as well as TRP channels of subfamily V type 2 (TRPV2) and subfamily A type 1 (TRPA1). TRPV1 and TRPV2 transcripts were shown to be expressed in rat hippocampal tissue. When tested on epileptiform neuronal spike activity in hippocampal brain slices exposed to a Mg(2+)-free solution using multielectrode arrays (MEAs), CBDV reduced both epileptiform burst amplitude and duration. The prototypical TRPV1 agonist, capsaicin, produced similar, although not identical effects. Capsaicin, but not CBDV, effects on burst amplitude were reversed by IRTX, a selective TRPV1 antagonist. These data suggest that CBDV antiepileptiform effects in the Mg(2+)-free model are not uniquely mediated via activation of TRPV1. However, TRPV1 was strongly phosphorylated (and hence likely sensitized) in Mg(2+)-free solution-treated hippocampal tissue, and both capsaicin and CBDV caused TRPV1 dephosphorylation, consistent with TRPV1 desensitization. We propose that CBDV effects on TRP channels should be studied further in different in vitro and in vivo models of epilepsy.

Database: PubMed

112. Cannabidiol: pharmacology and potential therapeutic role in epilepsy and other neuropsychiatric disorders.

Author(s): Devinsky O; Cilio MR; Cross H; Fernandez-Ruiz J; French J; Hill C; Katz R; Di Marzo V; Jutras-Aswad D; Notcutt WG; Martinez-Orgado J; Robson PJ; Rohrback BG; Thiele E; Whalley B; Friedman D

Source: Epilepsia; Jun 2014; vol. 55 (no. 6); p. 791-802

Publication Date: Jun 2014

Publication Type(s): Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov’t; Review

PubMedID: 24854329

Available  at Epilepsia –  from IngentaConnect – Open Access

Available  at Epilepsia –  from Wiley

Available  at Epilepsia –  from IngentaConnect

Available  at Epilepsia –  from Unpaywall

Abstract:To present a summary of current scientific evidence about the cannabinoid, cannabidiol (CBD) with regard to its relevance to epilepsy and other selected neuropsychiatric disorders. We summarize the presentations from a conference in which invited participants reviewed relevant aspects of the physiology, mechanisms of action, pharmacology, and data from studies with animal models and human subjects. Cannabis has been used to treat disease since ancient times. Δ(9) -Tetrahydrocannabinol (Δ(9) -THC) is the major psychoactive ingredient and CBD is the major nonpsychoactive ingredient in cannabis. Cannabis and Δ(9) -THC are anticonvulsant in most animal models but can be proconvulsant in some healthy animals. The psychotropic effects of Δ(9) -THC limit tolerability. CBD is anticonvulsant in many acute animal models, but there are limited data in chronic models. The antiepileptic mechanisms of CBD are not known, but may include effects on the equilibrative nucleoside transporter; the orphan G-protein-coupled receptor GPR55; the transient receptor potential of vanilloid type-1 channel; the 5-HT1a receptor; and the α3 and α1 glycine receptors. CBD has neuroprotective and antiinflammatory effects, and it appears to be well tolerated in humans, but small and methodologically limited studies of CBD in human epilepsy have been inconclusive. More recent anecdotal reports of high-ratio CBD:Δ(9) -THC medical marijuana have claimed efficacy, but studies were not controlled. CBD bears investigation in epilepsy and other neuropsychiatric disorders, including anxiety, schizophrenia, addiction, and neonatal hypoxic-ischemic encephalopathy. However, we lack data from well-powered double-blind randomized, controlled studies on the efficacy of pure CBD for any disorder. Initial dose-tolerability and double-blind randomized, controlled studies focusing on target intractable epilepsy populations such as patients with Dravet and Lennox-Gastaut syndromes are being planned. Trials in other treatment-resistant epilepsies may also be warranted. A PowerPoint slide summarizing this article is available for download in the Supporting Information section here.

Database: PubMed

113. The case for medical marijuana in epilepsy.

Author(s): Maa E; Figi P

Source: Epilepsia; Jun 2014; vol. 55 (no. 6); p. 783-786

Publication Date: Jun 2014

Publication Type(s): Case Reports; Journal Article

PubMedID: 24854149

Available  at Epilepsia –  from IngentaConnect – Open Access

Available  at Epilepsia –  from Wiley

Available  at Epilepsia –  from IngentaConnect

Available  at Epilepsia –  from Unpaywall

Abstract:Charlotte, a little girl with SCN1A-confirmed Dravet syndrome, was recently featured in a special that aired on CNN. Through exhaustive personal research and assistance from a Colorado-based medical marijuana group (Realm of Caring), Charlotte’s mother started adjunctive therapy with a high concentration cannabidiol/Δ(9) -tetrahydrocannabinol (CBD:THC) strain of cannabis, now known as Charlotte’s Web. This extract, slowly titrated over weeks and given in conjunction with her existing antiepileptic drug regimen, reduced Charlotte’s seizure frequency from nearly 50 convulsive seizures per day to now 2-3 nocturnal convulsions per month. This effect has persisted for the last 20 months, and Charlotte has been successfully weaned from her other antiepileptic drugs. We briefly review some of the history, preclinical and clinical data, and controversies surrounding the use of medical marijuana for the treatment of epilepsy, and make a case that the desire to isolate and treat with pharmaceutical grade compounds from cannabis (specifically CBD) may be inferior to therapy with whole plant extracts. Much more needs to be learned about the mechanisms of antiepileptic activity of the phytocannabinoids and other constituents of Cannabis sativa.

Database: PubMed

114. Systematic review: efficacy and safety of medical marijuana in selected neurologic disorders: report of the Guideline Development Subcommittee of the American Academy of Neurology.

Author(s): Koppel BS; Brust JC; Fife T; Bronstein J; Youssof S; Gronseth G; Gloss D

Source: Neurology; Apr 2014; vol. 82 (no. 17); p. 1556-1563

Publication Date: Apr 2014

Publication Type(s): Journal Article; Research Support, Non-U.S. Gov’t; Review; Systematic Review

PubMedID: 24778283

Available  at Neurology –  from American Academy of Neurology Please note that full text is not available for all the issues of this title.

Available  at Neurology –  from Unpaywall

Abstract:OBJECTIVE: To determine the efficacy of medical marijuana in several neurologic conditions.METHODS: We performed a systematic review of medical marijuana (1948-November 2013) to address treatment of symptoms of multiple sclerosis (MS), epilepsy, and movement disorders. We graded the studies according to the American Academy of Neurology classification scheme for therapeutic articles.RESULTS: Thirty-four studies met inclusion criteria; 8 were rated as Class I.CONCLUSIONS: The following were studied in patients with MS: (1) Spasticity: oral cannabis extract (OCE) is effective, and nabiximols and tetrahydrocannabinol (THC) are probably effective, for reducing patient-centered measures; it is possible both OCE and THC are effective for reducing both patient-centered and objective measures at 1 year. (2) Central pain or painful spasms (including spasticity-related pain, excluding neuropathic pain): OCE is effective; THC and nabiximols are probably effective. (3) Urinary dysfunction: nabiximols is probably effective for reducing bladder voids/day; THC and OCE are probably ineffective for reducing bladder complaints. (4) Tremor: THC and OCE are probably ineffective; nabiximols is possibly ineffective. (5) Other neurologic conditions: OCE is probably ineffective for treating levodopa-induced dyskinesias in patients with Parkinson disease. Oral cannabinoids are of unknown efficacy in non-chorea-related symptoms of Huntington disease, Tourette syndrome, cervical dystonia, and epilepsy. The risks and benefits of medical marijuana should be weighed carefully. Risk of serious adverse psychopathologic effects was nearly 1%. Comparative effectiveness of medical marijuana vs other therapies is unknown for these indications.

Database: PubMed

115. Cannabinoids for epilepsy.

Author(s): Gloss D; Vickrey B

Source: The Cochrane database of systematic reviews; Mar 2014 (no. 3); p. CD009270

Publication Date: Mar 2014

Publication Type(s): Journal Article; Meta-Analysis; Review; Systematic Review

PubMedID: 24595491

Available  at The Cochrane database of systematic reviews –  from Cochrane Collaboration (Wiley)

Available  at The Cochrane database of systematic reviews –  from Unpaywall

Abstract:BACKGROUND: Marijuana appears to have anti-epileptic effects in animals. It is not currently known if it is effective in patients with epilepsy. Some states in the United States of America have explicitly approved its use for epilepsy.OBJECTIVES: To assess the efficacy and safety of cannabinoids when used as monotherapy or add-on treatment for people with epilepsy.SEARCH METHODS: We searched the Cochrane Epilepsy Group Specialized Register (9 September 2013), Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library (2013, Issue 8), MEDLINE (Ovid) (9 September 2013), ISI Web of Knowledge (9 September 2013), CINAHL (EBSCOhost) (9 September 2013), and ClinicalTrials.gov (9 September 2013). In addition, we included studies we personally knew about that were not found by the searches, as well as searched the references in the identified studies.SELECTION CRITERIA: Randomized controlled trials (RCTs) whether blinded or not.DATA COLLECTION AND ANALYSIS: Two authors independently selected trials for inclusion and extracted the data. The primary outcome investigated was seizure freedom at one year or more, or three times the longest interseizure interval. Secondary outcomes included responder rate at six months or more, objective quality of life data, and adverse events.MAIN RESULTS: We found four randomized trial reports that included a total of 48 patients, each of which used cannabidiol as the treatment agent. One report was an abstract and another was a letter to the editor. Anti-epileptic drugs were continued in all studies. Details of randomisation were not included in any study report. There was no investigation of whether the control and treatment participant groups were the same or different. All the reports were low quality.The four reports only answered the secondary outcome about adverse effects. None of the patients in the treatment groups suffered adverse effects.AUTHORS’ CONCLUSIONS: No reliable conclusions can be drawn at present regarding the efficacy of cannabinoids as a treatment for epilepsy. The dose of 200 to 300 mg daily of cannabidiol was safely administered to small numbers of patients generally for short periods of time, and so the safety of long term cannabidiol treatment cannot be reliably assessed.

Database: PubMed

116. Report of a parent survey of cannabidiol-enriched cannabis use in pediatric treatment-resistant epilepsy.

Author(s): Porter BE; Jacobson C

Source: Epilepsy & behavior : E&B; Dec 2013; vol. 29 (no. 3); p. 574-577

Publication Date: Dec 2013

Publication Type(s): Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov’t

PubMedID: 24237632

Available  at Epilepsy & behavior : E&B –  from ClinicalKey

Available  at Epilepsy & behavior : E&B –  from Unpaywall

Abstract:Severe childhood epilepsies are characterized by frequent seizures, neurodevelopmental delays, and impaired quality of life. In these treatment-resistant epilepsies, families often seek alternative treatments. This survey explored the use of cannabidiol-enriched cannabis in children with treatment-resistant epilepsy. The survey was presented to parents belonging to a Facebook group dedicated to sharing information about the use of cannabidiol-enriched cannabis to treat their child’s seizures. Nineteen responses met the following inclusion criteria for the study: a diagnosis of epilepsy and current use of cannabidiol-enriched cannabis. Thirteen children had Dravet syndrome, four had Doose syndrome, and one each had Lennox-Gastaut syndrome and idiopathic epilepsy. The average number of antiepileptic drugs (AEDs) tried before using cannabidiol-enriched cannabis was 12. Sixteen (84%) of the 19 parents reported a reduction in their child’s seizure frequency while taking cannabidiol-enriched cannabis. Of these, two (11%) reported complete seizure freedom, eight (42%) reported a greater than 80% reduction in seizure frequency, and six (32%) reported a 25-60% seizure reduction. Other beneficial effects included increased alertness, better mood, and improved sleep. Side effects included drowsiness and fatigue. Our survey shows that parents are using cannabidiol-enriched cannabis as a treatment for their children with treatment-resistant epilepsy. Because of the increasing number of states that allow access to medical cannabis, its use will likely be a growing concern for the epilepsy community. Safety and tolerability data for cannabidiol-enriched cannabis use among children are not available. Objective measurements of a standardized preparation of pure cannabidiol are needed to determine whether it is safe, well tolerated, and efficacious at controlling seizures in this pediatric population with difficult-to-treat seizures.

Database: PubMed

117. Cannabis and other illicit drug use in epilepsy patients.

Author(s): Hamerle M; Ghaeni L; Kowski A; Weissinger F; Holtkamp M

Source: European journal of neurology; 2014; vol. 21 (no. 1); p. 167-170

Publication Date: 2014

Publication Type(s): Journal Article

PubMedID: 23311572

Available  at European journal of neurology –  from Wiley Online Library Medicine and Nursing Collection 2018 – NHS

Abstract:BACKGROUND AND PURPOSE: This study aimed to assess the prevalence of illicit drug use among epilepsy patients and its effects on the disease.METHODS: We systematically interviewed epilepsy outpatients at a tertiary epilepsy clinic. Predictors for active cannabis use were analysed with a logistic regression model.RESULTS: Overall, 310 subjects were enrolled; 63 (20.3%) reported consuming cannabis after epilepsy was diagnosed, and 16 (5.2%) used other illicit drugs. Active cannabis use was predicted by sex (male) [odds ratio (OR) 5.342, 95% confidence interval (95% CI) 1.416-20.153] and age (OR 0.956, 95% CI 0.919-0.994). Cannabis consumption mostly did not affect epilepsy (84.1%). Seizure worsening was observed with frequent illicit (non-cannabis) drug use in 80% of cases.CONCLUSIONS: Cannabis use does not seem to affect epilepsy; however, frequent use of other drugs increases seizure risk.

Database: PubMed

118. Seizure exacerbation in two patients with focal epilepsy following marijuana cessation.

Author(s): Hegde M; Santos-Sanchez C; Hess CP; Kabir AA; Garcia PA

Source: Epilepsy & behavior : E&B; Dec 2012; vol. 25 (no. 4); p. 563-566

Publication Date: Dec 2012

Publication Type(s): Case Reports; Journal Article

PubMedID: 23159379

Available  at Epilepsy & behavior : E&B –  from ClinicalKey

Abstract:While animal models of epilepsy suggest that exogenous cannabinoids may have anticonvulsant properties, scant evidence exists for these compounds’ efficacy in humans. Here, we report on two patients whose focal epilepsy was nearly controlled through regular outpatient marijuana use. Both stopped marijuana upon admission to our epilepsy monitoring unit (EMU) and developed a dramatic increase in seizure frequency documented by video-EEG telemetry. These seizures occurred in the absence of other provocative procedures, including changes to anticonvulsant medications. We review these cases and discuss mechanisms for the potentially anticonvulsant properties of cannabis, based on a review of the literature.

Database: PubMed

119. Cannabinoids for epilepsy.

Author(s): Gloss D; Vickrey B

Source: The Cochrane database of systematic reviews; Jun 2012 (no. 6); p. CD009270

Publication Date: Jun 2012

Publication Type(s): Journal Article; Meta-Analysis; Review; Systematic Review

PubMedID: 22696383

Available  at The Cochrane database of systematic reviews –  from Cochrane Collaboration (Wiley)

Available  at The Cochrane database of systematic reviews –  from Unpaywall

Abstract:BACKGROUND: Marijuana appears to have anti-epileptic effects in animals. It is not currently known if it is effective in patients with epilepsy. Some states in the United States of America have explicitly approved its use for epilepsy.OBJECTIVES: To assess the efficacy of marijuana, or one of marijuana’s constituents in the treatment of people with epilepsy.SEARCH METHODS: We searched the Cochrane Epilepsy Group Specialized Register (May 15, 2012), the Cochrane Central Register of Controlled Trials (CENTRAL issue 4 of 12, The Cochrane Library 2012),MEDLINE (PubMed, searched on May 15, 2012), ISI Web of Knowledge (May 15, 2012), CINAHL (EBSCOhost, May 15, 2012), and ClinicalTrials.gov (May 15, 2012). In addition, we included studies we personally knew about that were not found by the searches, as well as references in the identified studies.SELECTION CRITERIA: Randomized controlled trials (RCTs), whether blinded or not.DATA COLLECTION AND ANALYSIS: Two authors independently selected trials for inclusion and extracted data. The primary outcome investigated was seizure freedom at one year or more, or three times the longest interseizure interval. Secondary outcomes included: responder rate at six months or more, objective quality of life data, and adverse events.MAIN RESULTS: We found four randomized reports which included a total of 48 patients, each of which used cannabidiol as the treatment agent. One report was an abstract, and another was a letter to the editor. Anti-epileptic drugs were continued in all. Details of randomisation were not included in any study. There was no investigation of whether control and treatment groups were the same or different. All the reports were low quality.The four reports only answered the secondary outcome about adverse effects. None of the patients in the treatment groups suffered adverse effects.AUTHORS’ CONCLUSIONS: No reliable conclusions can be drawn at present regarding the efficacy of cannabinoids as a treatment for epilepsy. The dose of 200 to 300 mg daily of cannabidiol was safely administered to small numbers of patients, for generally short periods of time, and so the safety of long term cannabidiol treatment cannot be reliably assessed.

Database: PubMed

120. Cannabidiol for neurodegenerative disorders: important new clinical applications for this phytocannabinoid?

Author(s): Fernández-Ruiz J; Sagredo O; Pazos MR; García C; Pertwee R; Mechoulam R; Martínez-Orgado J

Source: British journal of clinical pharmacology; Feb 2013; vol. 75 (no. 2); p. 323-333

Publication Date: Feb 2013

Publication Type(s): Journal Article; Research Support, Non-U.S. Gov’t; Review

PubMedID: 22625422

Available  at British journal of clinical pharmacology –  from Europe PubMed Central – Open Access

Available  at British journal of clinical pharmacology –  from IngentaConnect – Open Access

Available  at British journal of clinical pharmacology –  from Wiley

Available  at British journal of clinical pharmacology –  from IngentaConnect

Available  at British journal of clinical pharmacology –  from Unpaywall

Abstract:Cannabidiol (CBD) is a phytocannabinoid with therapeutic properties for numerous disorders exerted through molecular mechanisms that are yet to be completely identified. CBD acts in some experimental models as an anti-inflammatory, anticonvulsant, anti-oxidant, anti-emetic, anxiolytic and antipsychotic agent, and is therefore a potential medicine for the treatment of neuroinflammation, epilepsy, oxidative injury, vomiting and nausea, anxiety and schizophrenia, respectively. The neuroprotective potential of CBD, based on the combination of its anti-inflammatory and anti-oxidant properties, is of particular interest and is presently under intense preclinical research in numerous neurodegenerative disorders. In fact, CBD combined with Δ(9)-tetrahydrocannabinol is already under clinical evaluation in patients with Huntington’s disease to determine its potential as a disease-modifying therapy. The neuroprotective properties of CBD do not appear to be exerted by the activation of key targets within the endocannabinoid system for plant-derived cannabinoids like Δ(9)-tetrahydrocannabinol, i.e. CB(1) and CB(2) receptors, as CBD has negligible activity at these cannabinoid receptors, although certain activity at the CB(2) receptor has been documented in specific pathological conditions (i.e. damage of immature brain). Within the endocannabinoid system, CBD has been shown to have an inhibitory effect on the inactivation of endocannabinoids (i.e. inhibition of FAAH enzyme), thereby enhancing the action of these endogenous molecules on cannabinoid receptors, which is also noted in certain pathological conditions. CBD acts not only through the endocannabinoid system, but also causes direct or indirect activation of metabotropic receptors for serotonin or adenosine, and can target nuclear receptors of the PPAR family and also ion channels.

Database: PubMed

121. Statistical parametric mapping reveals regional alterations in cannabinoid CB1 receptor distribution and G-protein activation in the 3D reconstructed epileptic rat brain.

Author(s): Sayers KW; Nguyen PT; Blair RE; Sim-Selley LJ; DeLorenzo RJ

Source: Epilepsia; May 2012; vol. 53 (no. 5); p. 897-907

Publication Date: May 2012

Publication Type(s): Journal Article; Research Support, N.I.H., Extramural

PubMedID: 22509801

Available  at Epilepsia –  from IngentaConnect – Open Access

Available  at Epilepsia –  from Wiley

Available  at Epilepsia –  from IngentaConnect

Available  at Epilepsia –  from Unpaywall

Abstract:PURPOSE:   The endocannabinoid system is known to modulate seizure activity in several in vivo and in vitro models, and CB(1) -receptor activation is anticonvulsant in the rat pilocarpine model of acquired epilepsy (AE). In these epileptic rats, a unique redistribution of the CB(1) receptor occurs within the hippocampus; however, an anatomically inclusive analysis of the effect of status epilepticus (SE)-induced AE on CB(1) receptors has not been thoroughly evaluated. Therefore, statistical parametric mapping (SPM), a whole-brain unbiased approach, was used to study the long-term effect of pilocarpine-induced SE on CB(1) -receptor binding and G-protein activation in rats with AE.METHODS:   Serial coronal sections from control and epileptic rats were cut at equal intervals throughout the neuraxis and processed for [(3) H]WIN55,212-2 (WIN) autoradiography, WIN-stimulated [(35) S]GTPγS autoradiography, and CB(1) -receptor immunohistochemistry (IHC). The autoradiographic techniques were evaluated with both region of interest (ROI) and SPM analyses.KEY FINDINGS:   In rats with AE, regionally specific increases in CB(1) -receptor binding and activity were detected in cortex, discrete thalamic nuclei, and other regions including caudate-putamen and septum, and confirmed by IHC. However, CB(1) receptors were unaltered in several brain regions, including substantia nigra and cerebellum, and did not exhibit regional decreases in rats with AE.SIGNIFICANCE:   This study provides the first comprehensive evaluation of the regional distribution of changes in CB(1) -receptor expression, binding, and G-protein activation in the rat pilocarpine model of AE. These regions may ultimately serve as targets for cannabinomimetic compounds or manipulation of the endocannabinoid system in epileptic brain.

Database: PubMed

122. Marijuana, endocannabinoids, and epilepsy: potential and challenges for improved therapeutic intervention.

Author(s): Hofmann ME; Frazier CJ

Source: Experimental neurology; Jun 2013; vol. 244 ; p. 43-50

Publication Date: Jun 2013

Publication Type(s): Journal Article; Research Support, N.I.H., Extramural; Review

PubMedID: 22178327

Available  at Experimental neurology –  from Unpaywall

Abstract:Phytocannabinoids isolated from the cannabis plant have broad potential in medicine that has been well recognized for many centuries. It is presumed that these lipid soluble signaling molecules exert their effects in both the central and peripheral nervous system in large part through direct interaction with metabotropic cannabinoid receptors. These same receptors are also targeted by a variety of endogenous cannabinoids including 2-arachidonoyl glycerol and anandamide. Significant effort over the last decade has produced an enormous advance in our understanding of both the cellular and the synaptic physiology of endogenous lipid signaling systems. This increase in knowledge has left us better prepared to carefully evaluate the potential for both natural and synthetic cannabinoids in the treatment of a variety of neurological disorders. In the case of epilepsy, long standing interest in therapeutic approaches that target endogenous cannabinoid signaling systems are, for the most part, not well justified by available clinical data from human epileptics. Nevertheless, basic science experiments have clearly indicated a key role for endogenous cannabinoid signaling systems in moment to moment regulation of neuronal excitability. Further it has become clear that these systems can both alter and be altered by epileptiform activity in a wide range of in vitro and in vivo models of epilepsy. Collectively these observations suggest clear potential for effective therapeutic modulation of endogenous cannabinoid signaling systems in the treatment of human epilepsy, and in fact, further highlight key obstacles that would need to be addressed to reach that goal.

Database: PubMed

123. Cerebrospinal fluid levels of the endocannabinoid anandamide are reduced in patients with untreated newly diagnosed temporal lobe epilepsy.

Author(s): Romigi A; Bari M; Placidi F; Marciani MG; Malaponti M; Torelli F; Izzi F; Prosperetti C; Zannino S; Corte F; Chiaramonte C; Maccarrone M

Source: Epilepsia; May 2010; vol. 51 (no. 5); p. 768-772

Publication Date: May 2010

Publication Type(s): Comparative Study; Journal Article

PubMedID: 19817812

Available  at Epilepsia –  from IngentaConnect – Open Access

Available  at Epilepsia –  from Wiley

Available  at Epilepsia –  from IngentaConnect

Abstract:PURPOSE: The endocannabinoid system is involved in excitatory/inhibitory balance mechanisms within the central nervous system (CNS). Growing evidence shows that its perturbation leads to development of epileptic seizures in experimental models, thus indicating that endocannabinoids play an intrinsic protective role in suppressing pathologic neuronal excitability. Experimental data also demonstrate that the endocannabinoid anandamide (AEA) can antagonize epileptic discharges in hippocampal tissue. The objective of our study was to measure endocannabinoids levels in the cerebrospinal fluid (CSF) of drug-naive patients affected by temporal lobe epilepsy (TLE).METHODS: We measured the levels of both AEA and the other endocannabinoid, 2-arachidonoylglycerol (2-AG), in the CSF of drug-naive patients with TLE.RESULTS: A significant reduction of AEA was found in the CSF of patients with compared with healthy controls (epileptic patients = 2.55 +/- 1.78 pmol/ml; healthy controls = 11.65 +/- 7.53 pmol/ml; n = 9 for both groups, p < 0.01). 2-AG levels, however, were not affected (epileptic patients = 209.5 +/- 146.56; healthy controls = 159.6 +/- 110.2) (n = 6 for both groups, p = 0.48).DISCUSSION: Our findings seem to be consistent with experimental evidence demonstrating a significant prevention of epileptic seizures induced by endocannabinoids in models of epilepsy. Furthermore, they support the hypothesis that AEA may be involved in its pathogenesis, suggesting a hypothetical primary impairment of the endocannabinoid system in untreated TLE. The actual role of this in vivo dysregulation still remains unclear.

Database: PubMed

124. Temporal characterization of changes in hippocampal cannabinoid CB(1) receptor expression following pilocarpine-induced status epilepticus.

Author(s): Falenski KW; Carter DS; Harrison AJ; Martin BR; Blair RE; DeLorenzo RJ

Source: Brain research; Mar 2009; vol. 1262 ; p. 64-72

Publication Date: Mar 2009

Publication Type(s): Journal Article; Research Support, N.I.H., Extramural

PubMedID: 19368833

Available  at Brain research –  from ClinicalKey

Abstract:Several reports have focused on the involvement of the endocannabinoid system in hyperexcitability, particularly in seizure and epilepsy models. Our laboratory recently characterized a novel plasticity change of the cannabinoid type 1 (CB(1)) receptor in hippocampi of epileptic rats following pilocarpine-induced status epilepticus (SE). This long-term redistribution included selective layer-specific changes in CB(1) receptor expression within distinct hippocampal subregions. However, the temporal characteristics of this redistribution during the development of epilepsy had not been examined. Therefore, this study was initiated to evaluate the time course by which pilocarpine-induced SE produced changes in CB(1) receptor expression. Immunohistochemical analysis demonstrated that within 1 week following SE, there was a pronounced loss in CB(1) receptor expression throughout the hippocampus, while staining in many interneurons was preserved. By 1 month post-SE, pilocarpine-treated animals began to display epileptic seizures, and CB(1) receptor expression was characteristic of the redistribution observed in long-term epileptic rats, with decreases in CB(1) receptor immunoreactivity in the stratum pyramidale neuropil and dentate gyrus inner molecular layer, and increases in the strata oriens and radiatum of CA1-3. Observed changes in CB(1) receptor expression were confirmed at multiple time points by western blot analysis. The data indicate that overall decreases in expression following SE preempt a long-lasting CB(1) receptor redistribution, and that differential responses occur within the hippocampus to initial CB(1) receptor losses. This suggests a role for dysregulation of the endocannabinoid system during epileptogenesis and indicates that the CB(1) receptor redistribution temporally correlates with the emergence of epileptic seizures.

Database: PubMed

125. Potential therapeutical effects of cannabidiol in children with pharmacoresistant epilepsy.

Author(s): Cortesi M; Fusar-Poli P

Source: Medical hypotheses; 2007; vol. 68 (no. 4); p. 920-921

Publication Date: 2007

Publication Type(s): Letter

PubMedID: 17112679

Available  at Medical hypotheses –  from ClinicalKey

Database: PubMed

126. The endocannabinoid system controls key epileptogenic circuits in the hippocampus.

Author(s): Monory K; Massa F; Egertová M; Eder M; Blaudzun H; Westenbroek R; Kelsch W; Jacob W; Marsch R; Ekker M; Long J; Rubenstein JL; Goebbels S; Nave KA; During M; Klugmann M; Wölfel B; Dodt HU; Zieglgänsberger W; Wotjak CT; Mackie K; Elphick MR; Marsicano G; Lutz B

Source: Neuron; Aug 2006; vol. 51 (no. 4); p. 455-466

Publication Date: Aug 2006

Publication Type(s): Comparative Study; Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov’t

PubMedID: 16908411

Available  at Neuron –  from ProQuest (Hospital Premium Collection) – NHS Version

Available  at Neuron –  from ScienceDirect (Cell Press Free Full Text)

Abstract:Balanced control of neuronal activity is central in maintaining function and viability of neuronal circuits. The endocannabinoid system tightly controls neuronal excitability. Here, we show that endocannabinoids directly target hippocampal glutamatergic neurons to provide protection against acute epileptiform seizures in mice. Functional CB1 cannabinoid receptors are present on glutamatergic terminals of the hippocampal formation, colocalizing with vesicular glutamate transporter 1 (VGluT1). Conditional deletion of the CB1 gene either in cortical glutamatergic neurons or in forebrain GABAergic neurons, as well as virally induced deletion of the CB1 gene in the hippocampus, demonstrate that the presence of CB1 receptors in glutamatergic hippocampal neurons is both necessary and sufficient to provide substantial endogenous protection against kainic acid (KA)-induced seizures. The direct endocannabinoid-mediated control of hippocampal glutamatergic neurotransmission may constitute a promising therapeutic target for the treatment of disorders associated with excessive excitatory neuronal activity.

Database: PubMed

127. Not too excited? Thank your endocannabinoids.

Author(s): Alger BE

Source: Neuron; Aug 2006; vol. 51 (no. 4); p. 393-395

Publication Date: Aug 2006

Publication Type(s): Comment; Journal Article

PubMedID: 16908404

Available  at Neuron –  from ProQuest (Hospital Premium Collection) – NHS Version

Available  at Neuron –  from ScienceDirect (Cell Press Free Full Text)

Available  at Neuron –  from Unpaywall

Abstract:Endocannabinoids can mediate neuroprotection, but it is not known how. In this issue of Neuron, Monory et al. use mutant mice and localized viral targeting to produce conditional knockouts of the cannabinoid CB1 receptor. They show that protection against kainic acid-induced seizures and cell death is conferred by CB1Rs on hippocampal glutamatergic nerve terminals.

Database: PubMed

128. Endocannabinoids and their implications for epilepsy.

Author(s): Alger BE

Source: Epilepsy currents; 2004; vol. 4 (no. 5); p. 169-173

Publication Date: 2004

Publication Type(s): Journal Article

PubMedID: 16059489

Available  at Epilepsy currents –  from Europe PubMed Central – Open Access

Available  at Epilepsy currents –  from Unpaywall

Abstract:This review covers the main features of a newly discovered intercellular signaling system in which endogenous ligands of the brain’s cannabinoid receptors, or endocannabinoids, serve as retrograde messengers that enable a cell to control the strength of its own synaptic inputs. Endocannabinoids are released by bursts of action potentials, including events resembling interictal spikes, and probably by seizures as well. Activation of cannabinoid receptors has been implicated in neuroprotection against excitotoxicity and can help explain the anticonvulsant properties of cannabinoids that have been known since antiquity.

Database: PubMed

129. Cannabinoids as potential anti-epileptic drugs.

Author(s): Smith PF

Source: Current opinion in investigational drugs (London, England : 2000); Jul 2005; vol. 6 (no. 7); p. 680-685

Publication Date: Jul 2005

Publication Type(s): Journal Article; Review

PubMedID: 16044663

Abstract:Cannabinoids have long been recognized as having the potential for both anticonvulsant and proconvulsant effects. The increased understanding of the cannabinoid receptors and their endogenous ligands over the last decade has provided a potential mechanism of action for these apparently paradoxical effects. Although the anticonvulsant effects of cannabinoids appear to be mediated by their action at presynaptic cannabinoid receptors, which inhibit the release of excitatory neurotransmitters such as glutamate, it is clear that they are also capable of producing proconvulsant effects through the activation of cannabinoid receptors on terminals releasing inhibitory neurotransmitters, such as gamma-amino-butyric acid. In the brain, the activation of cannabinoid receptors is carefully controlled by the rapid synthesis and degradation of endocannabinoids in a way that targets the endogenous ligands to specific sets of cannabinoid receptors. The potential problem in delivering a cannabinoid drug to treat epilepsy is the inability to control its actions at different cannabinoid receptors regulating the release of different neurotransmitters. Since the action of cannabinoids is complex, and there is a dearth of clinical trial data, it is currently unclear whether cannabinoids might be both efficacious and safe in the treatment of epilepsy.

Database: PubMed

130. On-demand activation of the endocannabinoid system in the control of neuronal excitability and epileptiform seizures.

Author(s): Lutz B

Source: Biochemical pharmacology; Nov 2004; vol. 68 (no. 9); p. 1691-1698

Publication Date: Nov 2004

Publication Type(s): Journal Article; Research Support, Non-U.S. Gov’t; Review

PubMedID: 15450934

Abstract:Neurons intensively exchange information among each other using both inhibitory and excitatory neurotransmitters. However, if the balance of excitation and inhibition is perturbed, the intensity of excitatory transmission may exceed a certain threshold and epileptic seizures can occur. As the occurrence of epilepsy in the human population is about 1%, the search for therapeutic targets to alleviate seizures is warranted. Extracts of Cannabis sativa have a long history in the treatment of various neurological diseases, including epilepsy. However, cannabinoids have been reported to exert both pro- and anti-convulsive activities. The recent progress in understanding the endogenous cannabinoid system has allowed new insights into these opposing effects of cannabinoids. When excessive neuronal activity occurs, endocannabinoids are generated on demand and activate cannabinoid type 1 (CB1) receptors. Using mice lacking CB1 receptors in principal forebrain neurons in a model of epileptiform seizures, it was shown that CB1 receptors expressed on excitatory glutamatergic neurons mediate the anti-convulsive activity of endocannabinoids. Systemic activation of CB1 receptors by exogenous cannabinoids, however, are anti- or pro-convulsive, depending on the seizure model used. The pro-convulsive activity of exogenous cannabinoids might be explained by the notion that CB1 receptors expressed on inhibitory GABAergic neurons are also activated, leading to a decreased release of GABA, and to a concomitant increase in seizure susceptibility. The concept that the endogenous cannabinoid system is activated on demand suggests that a promising strategy to alleviate seizure frequency is the enhancement of endocannabinoid levels by inhibiting the cellular uptake and the degradation of these endogenous compounds.

Database: PubMed

131. Marijuana use and epilepsy: prevalence in patients of a tertiary care epilepsy center.

Author(s): Gross DW; Hamm J; Ashworth NL; Quigley D

Source: Neurology; Jun 2004; vol. 62 (no. 11); p. 2095-2097

Publication Date: Jun 2004

Publication Type(s): Journal Article; Research Support, Non-U.S. Gov’t

PubMedID: 15184622

Available  at Neurology –  from American Academy of Neurology Please note that full text is not available for all the issues of this title.

Abstract:The authors sought to determine the prevalence of marijuana use in patients with epilepsy by performing a telephone survey in a tertiary care epilepsy center. Twenty-one percent of subjects had used marijuana in the past year with the majority of active users reporting beneficial effects on seizures. Twenty-four percent of all subjects believed marijuana was an effective therapy for epilepsy. Despite limited evidence of efficacy, many patients with epilepsy believe marijuana is an effective therapy for epilepsy and are actively using it.

Database: PubMed

132. On the application of cannabis in paediatrics and epileptology.

Author(s): Lorenz R

Source: Neuro endocrinology letters; 2004; vol. 25 (no. 1-2); p. 40-44

Publication Date: 2004

Publication Type(s): Case Reports; Journal Article

PubMedID: 15159680

Abstract:An initial report on the therapeutic application of delta 9-THC (THC) (Dronabinol, Marinol) in 8 children resp. adolescents suffering from the following conditions, is given: neurodegenerative disease, mitochondriopathy, posthypoxic state, epilepsy, posttraumatic reaction. THC effected reduced spasticity, improved dystonia, increased initiative (with low dose), increased interest in the surroundings, and anticonvulsive action. The doses ranged from 0.04 to 0.12 mg/kg body weight a day. The medication was given as an oily solution orally in 7 patients, via percutaneous gastroenterostomy tube in one patient. At higher doses disinhibition and increased restlessness were observed. In several cases treatment was discontinued and in none of them discontinuing resulted in any problems. The possibility that THC-induced effects on ion channels and transmitters may explain its therapeutic activity seen in epileptic patients is discussed.

Database: PubMed

133. The endogenous cannabinoid system regulates seizure frequency and duration in a model of temporal lobe epilepsy.

Author(s): Wallace MJ; Blair RE; Falenski KW; Martin BR; DeLorenzo RJ

Source: The Journal of pharmacology and experimental therapeutics; Oct 2003; vol. 307 (no. 1); p. 129-137

Publication Date: Oct 2003

Publication Type(s): Journal Article; Research Support, U.S. Gov’t, P.H.S.

PubMedID: 12954810

Available  at The Journal of pharmacology and experimental therapeutics –  from HighWire – Free Full Text

Abstract:Several lines of evidence suggest that cannabinoid compounds are anticonvulsant. However, the anticonvulsant potential of cannabinoids and, moreover, the role of the endogenous cannabinoid system in regulating seizure activity has not been tested in an in vivo model of epilepsy that is characterized by spontaneous, recurrent seizures. Here, using the rat pilocarpine model of epilepsy, we show that the marijuana extract Delta9-tetrahydrocannabinol (10 mg/kg) as well as the cannabimimetic, 4,5-dihydro-2-methyl-4(4-morpholinylmethyl)-1-(1-naphthalenyl-carbonyl)-6H-pyrrolo[3,2,1-i,j]quinolin-6-one [R(+)WIN55,212 (5 mg/kg)], completely abolished spontaneous epileptic seizures. Conversely, application of the cannabinoid CB1 receptor (CB1) antagonist, N-(piperidin-1-yl-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamidehydrochloride (SR141716A), significantly increased both seizure duration and frequency. In some animals, CB1 receptor antagonism resulted in seizure durations that were protracted to a level consistent with the clinical condition status epilepticus. Furthermore, we determined that during an short-term pilocarpine-induced seizure, levels of the endogenous CB1 ligand 2-arachidonylglycerol increased significantly within the hippocampal brain region. These data indicate not only anticonvulsant activity of exogenously applied cannabinoids but also suggest that endogenous cannabinoid tone modulates seizure termination and duration through activation of the CB1 receptor. Furthermore, Western blot and immunohistochemical analyses revealed that CB1 receptor protein expression was significantly increased throughout the CA regions of epileptic hippocampi. By demonstrating a role for the endogenous cannabinoid system in regulating seizure activity, these studies define a role for the endogenous cannabinoid system in modulating neuroexcitation and suggest that plasticity of the CB1 receptor occurs with epilepsy.

Database: PubMed

134. Cannabinoid receptor-1 activation suppresses inhibitory synaptic activity in human dentate gyrus.

Author(s): Nakatsuka T; Chen HX; Roper SN; Gu JG

Source: Neuropharmacology; Jul 2003; vol. 45 (no. 1); p. 116-121

Publication Date: Jul 2003

Publication Type(s): Journal Article; Research Support, Non-U.S. Gov’t; Research Support, U.S. Gov’t, Non-P.H.S.; Research Support, U.S. Gov’t, P.H.S.

PubMedID: 12814664

Abstract:In spite of their popular uses as recreational drugs and their potential therapeutic uses, little direct information has been obtained about the synaptic effects of cannabinoids in the human brain. In the present study, patch-clamp recordings were performed on granule cells of the human dentate gyrus and the effects of cannabinoid receptor-1 (CB1) activation on inhibitory synaptic activity were examined. Activation of CB1 receptors by WIN55212-2 significantly suppressed both frequency and amplitude of spontaneous inhibitory synaptic currents (IPSCs) to about 50% of control. The suppressive effects were completely abolished in the presence of the CB1 receptor antagonist, AM251. WIN55212-2 also suppressed evoked IPSCs. However, neither frequency nor amplitude of miniature IPSCs were affected by WIN55212-2. These results provide electrophysiological evidence for the role of CB1 receptors in modulating inhibitory activity in human dentate gyrus.

Database: PubMed

135. Alcohol and marijuana: effects on epilepsy and use by patients with epilepsy.

Author(s): Gordon E; Devinsky O

Source: Epilepsia; Oct 2001; vol. 42 (no. 10); p. 1266-1272

Publication Date: Oct 2001

Publication Type(s): Journal Article; Review

PubMedID: 11737161

Available  at Epilepsia –  from IngentaConnect – Open Access

Available  at Epilepsia –  from Wiley

Available  at Epilepsia –  from IngentaConnect

Abstract:We review the safety of alcohol or marijuana use by patients with epilepsy. Alcohol intake in small amounts (one to two drinks per day) usually does not increase seizure frequency or significantly affect serum levels of antiepileptic drugs (AEDs). Adult patients with epilepsy should therefore be allowed to consume alcohol in limited amounts. However, exceptions may include patients with a history of alcohol or substance abuse, or those with a history of alcohol-related seizures. The most serious risk of seizures in connection with alcohol use is withdrawal. Alcohol withdrawal lowers the seizure threshold, an effect that may be related to alcohol dose, rapidity of withdrawal, and chronicity of exposure. Individuals who chronically abuse alcohol are at significantly increased risk of developing seizures, which can occur during withdrawal or intoxication. Alcohol abuse predisposes to medical and metabolic disorders that can lower the seizure threshold or cause symptoms that mimic seizures. Therefore, in evaluating a seizure in a patient who is inebriated or has abused alcohol, one must carefully investigate to determine the cause. Animal and human research on the effects of marijuana on seizure activity are inconclusive. There are currently insufficient data to determine whether occasional or chronic marijuana use influences seizure frequency. Some evidence suggests that marijuana and its active cannabinoids have antiepileptic effects, but these may be specific to partial or tonic-clonic seizures. In some animal models, marijuana or its constituents can lower the seizure threshold. Preliminary, uncontrolled clinical studies suggest that cannabidiol may have antiepileptic effects in humans. Marijuana use can transiently impair short-term memory, and like alcohol use, may increase noncompliance with AEDs. Marijuana use or withdrawal could potentially trigger seizures in susceptible patients.

Database: PubMed

136. Hypnotic and antiepileptic effects of cannabidiol.

Author(s): Carlini EA; Cunha JM

Source: Journal of clinical pharmacology; 1981; vol. 21 (no. S1); p. 417S-427S

Publication Date: 1981

Publication Type(s): Clinical Trial; Journal Article

PubMedID: 7028792

Abstract:Clinical trials with cannabidiol (CBD) in healthy volunteers, isomniacs, and epileptic patients conducted in the authors’ laboratory from 1972 up to the present are reviewed. Acute doses of cannabidiol ranging from 10 to 600 mg and chronic administration of 10 mg for 20 days or 3 mg/kg/day for 30 days did not induce psychologic or physical symptoms suggestive of psychotropic or toxic effects; however, several volunteers complained of somnolence. Complementary laboratory tests (EKG, blood pressure, and blood and urine analysis) revealed no sign of toxicity. Doses of 40, 80, and 160 mg cannabidiol were compared to placebo and 5 mg nitrazepam in 15 insomniac volunteers. Subjects receiving 160 mg cannabidiol reported having slept significantly more than those receiving placebo; the volunteers also reported significantly less dream recall; with the three doses of cannabidiol than with placebo. Fifteen patients suffering from secondary generalized epilepsy refractory to known antiepileptic drugs received either 200 to 300 mg cannabidiol daily or placebo for as long as 4.5 months. Seven out of the eight epileptics receiving cannabidiol had improvement of their disease state, whereas only one placebo patient improved.

Database: PubMed

137. The cannabinoids as potential antiepileptics.

Author(s): Karler R; Turkanis SA

Source: Journal of clinical pharmacology; 1981; vol. 21 (no. S1); p. 437S-448S

Publication Date: 1981

Publication Type(s): Journal Article; Research Support, U.S. Gov’t, P.H.S.

PubMedID: 6975285

Abstract:Comparative studies of the anticonvulsant properties of the cannabinoids and prototype antiepileptic drugs in numerous animal seizure models demonstrate that (1) as an anticonvulsant, cannabidiol (CBD), in contrast to delta 9-tetrahydrocannabinol (THC), is relatively selective in terms of both central nervous system (CNS), depressant and excitatory properties; (2) the potency of cannabidiol, unlike that of phenytoin and phenobarbital, varies greatly with the species; (3) the large potency difference between the cannabinoids and the antiepileptics in the mouse appears to be due to dispositional differences, because brain concentrations of all the drugs are very similar; (4) tolerance to the anticonvulsant properties of cannabidiol is not a prominent feature; in three seizure models, tolerance developed in one, but “reverse tolerance” developed in the other two; and (5) the results of a study of the electrophysiologic mechanisms of action indicate that cannabidiol produces some unique effects and that its spectrum of antiepileptic activity may be different from that of the prototype drugs. The anticonvulsant nature of cannabidiol suggests that it has a therapeutic potential in at least three of the four major types of epilepsy: grand mal, cortical focal, and complex partial seizures.

Database: PubMed

138. Chronic administration of cannabidiol to healthy volunteers and epileptic patients.

Author(s): Cunha JM; Carlini EA; Pereira AE; Ramos OL; Pimentel C; Gagliardi R; Sanvito WL; Lander N; Mechoulam R

Source: Pharmacology; 1980; vol. 21 (no. 3); p. 175-185

Publication Date: 1980

Publication Type(s): Clinical Trial; Journal Article; Randomized Controlled Trial; Research Support, U.S. Gov’t, P.H.S.

PubMedID: 7413719

Abstract:In phase 1 of the study, 3 mg/kg daily of cannabidiol (CBD) was given for 30 days to 8 health human volunteers. Another 8 volunteers received the same number of identical capsules containing glucose as placebo in a double-blind setting. Neurological and physical examinations, blood and urine analysis, ECG and EEG were performed at weekly intervals. In phase 2 of the study, 15 patients suffering from secondary generalized epilepsy with temporal focus were randomly divided into two groups. Each patient received, in a double-blind procedure, 200-300 mg daily of CBD or placebo. The drugs were administered for along as 4 1/2 months. Clinical and laboratory examinations, EEG and ECG were performed at 15- or 30-day intervals. Throughout the experiment the patients continued to take the antiepileptic drugs prescribed before the experiment, although these drugs no longer controlled the signs of the disease. All patients and volunteers tolerated CBD very well and no signs of toxicity or serious side effects were detected on examination. 4 of the 8 CBD subjects remained almost free of convulsive crises throughout the experiment and 3 other patients demonstrated partial improvement in their clinical condition. CBD was ineffective in 1 patient. The clinical condition of 7 placebo patients remained unchanged whereas the condition of 1 patient clearly improved. The potential use of CBD as an antiepileptic drug and its possible potentiating effect on other antiepileptic drugs are discussed.

Database: PubMed

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1 thought on “A list of all the studies on epilepsy and cannabinoids

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